* 184745

KIT LIGAND; KITLG


Alternative titles; symbols

KL; KITL
MAST CELL GROWTH FACTOR; MGF
MGF STEM CELL FACTOR; SCF
STEEL, MOUSE, HOMOLOG OF
STEEL FACTOR; SF


HGNC Approved Gene Symbol: KITLG

Cytogenetic location: 12q21.32     Genomic coordinates (GRCh38): 12:88,492,793-88,580,471 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12q21.32 [Skin/hair/eye pigmentation 7, blond/brown hair] 611664 3
Deafness, autosomal dominant 69, unilateral or asymmetric 616697 AD 3
Hyperpigmentation with or without hypopigmentation 145250 AD 3
Waardenburg syndrome, type 2F 619947 AR 3

TEXT

Description

KITLG and its receptor, KIT (164920), function in hematopoiesis, melanogenesis, and gametogenesis (Rothschild et al., 2003).


Cloning and Expression

Stem cell factor is a hematopoietic growth factor and ligand for the KIT tyrosine kinase receptor. In the mouse, this growth factor is encoded by Sl ('steel'), a gene critical to the development of several distinct cell lineages during embryonic life as well as having important effects on hematopoiesis in the adult animal. Steel factor (SF) is a synonym for stem cell factor. The steel-Dickie mutation in the mouse, symbolized Sl(d), was shown by Brannan et al. (1991) to consist of a 4-kb intragenic deletion in mast cell growth factor (MGF) genomic sequences. As a consequence of the deletion, a soluble truncated growth factor was formed that lacked both transmembrane and cytoplasmic domains. The results provided direct evidence that Sl encodes MGF.

Using probes based on the sequence of rat Scf, Martin et al. (1990) isolated cDNA and genomic clones of human SCF. The deduced 248-amino acid human protein has an N-terminal signal sequence, a predicted transmembrane domain near the C terminus, and 5 predicted N-glycosylation sites. Northern blot analysis detected a 6-kb SCF transcript in a human fibrosarcoma cell line.

Huang et al. (1992) cloned full-length mouse Kitl, which they called Kl1, and a Kitl splice variant, which they called Kl2. Kl2 encodes an isoform lacking a 28-amino acid sequence preceding the transmembrane region of Kl1. RT-PCR and RNase protection assays revealed tissue-specific expression patterns for both Kl1 and Kl2. Using transfected COS-1 cells, Huang et al. (1992) showed that proteolytic cleavage of the Kl1 transmembrane precursor generated a soluble, biologically active form of Kl. Kl2 also produced a soluble, biologically active form of Kl, but with somewhat diminished efficiency. Proteolytic processing of both the Kl1 and Kl2 transmembrane proteins occurred on the cell surface.

Using RT-PCR, Zazo Seco et al. (2015) assessed transcription of Kitl in mouse cochlea and obtained 2 amplification products that corresponded to Kitl transcripts with and without exon 6. In addition, qPCR demonstrated that the relative levels of both Kitl alternative transcripts were higher at postnatal day 28 than at postnatal day 2. Zazo Seco et al. (2015) suggested that Kitl functions postnatally in the mouse inner ear.


Mapping

The Sl locus maps to the distal region of mouse chromosome 10 (Shimizu et al., 1992), in the vicinity of genes that have been mapped to human chromosome 12. On the basis of analysis of somatic cell hybrids between human cells and either hamster or mouse cells, Geissler et al. (1991) reported that the human gene maps to 12q14.3-qter. Mathew et al. (1992) regionalized the MGF gene to 12q22 by in situ hybridization.


Gene Function

Martin et al. (1990) found that SCF augmented the proliferation of both myeloid and lymphoid hematopoietic progenitors in bone marrow cultures.

Using Western blot and immunohistochemical analyses, Vincent et al. (1998) found that membrane-bound Kl2 was the major Kl isoform expressed in mouse testis and on mouse Sertoli cells. At stages VII to VIII, when spermatocytes enter meiosis, Kl2 was expressed on Sertoli cells from the peripheral to the adluminal compartment of the tubule. Kit was also expressed on the surface of germ cells up to the pachytene stage. Blocking interaction of Kl2 with Kit via blocking antibody or treatment with soluble Kl protein inhibited the appearance of haploid cells and completion of meiosis.

Rothschild et al. (2003) found that steroidogenesis in mouse Leydig cells was dependent on Kitl signaling and involved phosphoinositide 3-kinase (PI3K). Leydig cells of mice expressing mutant Kit unable to bind the p85 subunit of PI3K (PIK3R1; 171833) were unable to respond effectively to Kitl stimulation; however, mutant animals had normal serum testosterone levels. The findings suggested a model in which the mutant Leydig cells initially produce lower levels of testosterone, reducing testosterone negative feedback on the hypothalamic-pituitary axis, which leads to elevated luteinizing hormone (LH; see 152780) secretion and restoration of normal serum testosterone levels. Rothschild et al. (2003) concluded that KITL, acting via PI3K, is a paracrine regulator of Leydig cell steroidogenesis.

Matsuzawa et al. (2003) found that incubation of CD34 (142230)-positive/CD38 (107270)-positive cord blood cells with IL9 (146931) and SCF increased both the number and size of mast cell colonies compared with incubation of these cells with SCF alone. There was no difference in progeny generation between 6-week cultured mast cells incubated with IL9 and SCF and those incubated with SCF alone. IL9 and SCF increased mast cell colony numbers in peripheral blood cells, and did so more in cells from asthmatic patients than in cells from normal control children. Matsuzawa et al. (2003) concluded that IL9 is a potent enhancer of SCF-dependent growth of human mast cell progenitors.

Using Scf(gfp) knockin mice, Ding et al. (2012) found that SCF was primarily expressed by perivascular cells throughout the bone marrow. Hematopoietic stem cell (HSC) frequency and function were not affected when Scf was conditionally deleted from hematopoietic cells, osteoblasts, or nestin-cre- or nestin-creER-expressing cells. However, HSCs were depleted from bone marrow when Scf was deleted from endothelial cells or leptin receptor (LEPR; 601007)-expressing perivascular stromal cells. Most HSCs were lost when Scf was deleted from both endothelial and Lepr-expressing perivascular cells. Ding et al. (2012) concluded that HSCs reside in a perivascular niche in which multiple cell types express factors that promote HSC maintenance.

Inra et al. (2015) assessed the sources of the extramedullary hematopoiesis niche factors Scf and Cxcl12 (600835) in the mouse spleen after induction by myeloablation, blood loss, or pregnancy. In each case, Scf was expressed by endothelial cells and Tcf21 (603306)-positive stromal cells, primarily around sinusoids in the red pulp, while Cxcl12 was expressed by a subset of Tcf21-positive stromal cells. Extramedullary hematopoiesis induction markedly expanded the Scf-expressing endothelial cells and stromal cells by inducing proliferation. Most splenic HSCs were adjacent to Tcf21-positive stromal cells in red pulp. Conditional deletion of Scf from spleen endothelial cells, or of Scf or Cxcl12 from Tcf21-positive stromal cells, severely reduced spleen extramedullary hematopoiesis and reduced blood cell counts without affecting bone marrow hematopoiesis. Inra et al. (2015) concluded that endothelial cells and Tcf21-positive stromal cells thus create a perisinusoidal extramedullary hematopoiesis niche in the spleen, which is necessary for the physiologic response to diverse hematopoietic stresses.

Liao et al. (2017) found that mice with conditional deletion of Scf in Krox20 (129010) lineage cells exhibited progressive hair graying and lost all hair pigmentation early in life, suggesting that Krox20 lineage cells were the main source of Scf for follicular melanocytes to produce hair pigment. Depletion of Scf in epithelial cells of mice completely abolished hair pigmentation. Lacz reporter analysis suggested that hair pigmentation was regulated by Scf expression in hair shaft progenitor cells in the hair matrix. These hair shaft progenitors in the matrix were differentiated from follicular epithelial cells expressing Krox20. Liao et al. (2017) concluded that their study delineated the origin of SCF expression in hair matrix progenitors as a niche for follicular mature melanocytes and that their SCF is indispensible for hair pigmentation.


Molecular Genetics

Normal Skin/Hair/Eye Pigmentation Variation

Sulem et al. (2007) carried out a genomewide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun, and freckling among 2,986 Icelanders. The closely associated SNPs from 6 regions were replicated in a second sample of Icelanders and a sample of Dutch. The SNPs from all 6 regions met the criteria for genomewide significance. Sulem et al. (2007) found that a variant near KITLG (184745.0001) was associated with hair color (611664) in a genomewide association scan in Icelanders and Dutch.

Miller et al. (2007) investigated parallel origins in pigmentation changes in stickleback fish and humans. Using high-resolution mapping and expression experiments, they mapped light gills and ventrums in fish to a divergent regulatory allele of the Kitlg gene. European and East Asian humans also share derived alleles at the KITLG locus. For the rs642742 SNP (184745.0002), located 326 kb upstream of the KITLG transcription start site, the frequency of the ancestral A allele is at least 92% in West Africans, whereas the frequency of the derived G allele is at least 86% in Europeans and East Asians. Admixture mapping suggested that replacement of AA with GG in the rs642742 SNP may account for a lightening of a person's skin by 6 to 7 melanin units (see 611664). In comparison, the overall skin reflectance difference between West Africans and Europeans is 30 melanin units.

Familial Progressive Hyperpigmentation with or without Hypopigmentation

In a 6-generation Chinese family with progressive hyperpigmentation (FPHH; 145250), Wang et al. (2009) identified a missense mutation in the KITLG gene (N36S; 184745.0003). This mutation resulted in a gain of function and increased the content of melanin by 109% compared with wildtype KITLG in human melanoma cells. Consistent with this result, tyrosinase (606933) activity was significantly increased by the mutant compared with wildtype.

In affected individuals from 4 families with FPHH, Amyere et al. (2011) identified heterozygosity for missense mutations in the KITLG gene (184745.0003-184745.0005).

Deafness, Autosomal Dominant 69

In a large 5-generation Dutch family segregating autosomal dominant nonsyndromic hearing loss mapping to chromosome 12q21.32-q23.1 (DFNA69; 616697), Zazo Seco et al. (2015) identified a heterozygous frameshift mutation in the KITLG gene (184745.0006) that was present in all affected individuals. The mutation was also present in 4 unaffected obligate carriers, as well as 1 additional unaffected individual and another with unknown disease status, for a calculated penetrance rate of 60 to 67%. All evaluated family members had skin type I or II, blond hair, and blue eyes; hypo- or depigmentation of the skin was not observed in the younger generation, and changes seen in older generations appeared to be age-related and did not segregate with hearing loss. One affected individual who had hair and eye color lighter than other family members was also heterozygous for the G allele of SNP rs12821256 (184745.0001). Analysis of KITLG in a panel of 23 unrelated probands with autosomal dominant nonsyndromic unilateral or asymmetric hearing loss identified a Spanish father and son with an in-frame deletion in the KITLG gene (184745.0007), neither of whom exhibited hypo- or hyperpigmentation of the skin.

Waardenburg Syndrome, Type 2F

In a 16-year-old boy of Filipino ancestry with Waardenburg syndrome type 2F (WS2F; 619947) manifest as sensorineural deafness, brilliant blue irises, and hypopigmentation of the lower extremities, Ogawa et al. (2017) identified homozygosity for a missense mutation in the KITLG gene (R32C; 184745.0009) that segregated with disease in the family and was not found in public variant databases.

Using GeneMatcher, Vona et al. (2022) identified 6 unrelated children who had homozygous mutations in the KITLG gene (see, e.g., 184745.0009-184745.0011) and features consistent with WS2. All 6 probands had sensorineural hearing loss and pigmentary abnormalities of the hair and skin, and 5 also had pigmentary changes of the iris. Two of the probands were homozygous for the same R32C variant that had previously been reported in a Filipino boy with WS2 by Ogawa et al. (2017). The variants segregated with disease in the respective families and were either not found or were present at very low minor allele frequency in public variant databases.

Associations Pending Confirmation

A heterozygous variant in the KITLG gene (184745.0008) has been reported in a patient exhibiting features consistent with Waardenburg syndrome-2 (WS2; see 193510).

For discussion of a possible association between variation in the KITLG gene and testicular germ cell tumors, see 273300.


Animal Model

Matrix metalloproteinase-9 (MMP9; 120361), induced in bone marrow cells, releases soluble KITLG, permitting the transfer of endothelial and hematopoietic stem cells (HSCs) from the quiescent to proliferative niche. Heissig et al. (2002) found that bone marrow ablation in wildtype Mmp9 mice induced Sdf1 (600835), which upregulated Mmp9 expression and caused shedding of Kitl and recruitment of Kit-positive stem/progenitors. In Mmp9 -/- mice, release of Kitl and HSC motility were impaired, resulting in failure of hematopoietic recovery and increased mortality, while exogenous Kitl restored hematopoiesis and survival after bone marrow ablation. Release of Kitl by Mmp9 enabled bone marrow repopulating cells to translocate to a permissive vascular niche favoring differentiation and reconstitution of the stem/progenitor cell pool.


ALLELIC VARIANTS ( 11 Selected Examples):

.0001 SKIN/HAIR/EYE PIGMENTATION 7, BLOND/BROWN HAIR

KITLG, T-C (rs12821256)
  
RCV000013659

In a genomewide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun, and freckling in Icelandic and Dutch population samples, Sulem et al. (2007) found that the C allele of a single SNP on 12q21.33, rs12821256, showed genomewide significance in the initial scan for blond versus brown hair (OR = 2.32, P = 1.9 x 10(-14)) (611664). This association was confirmed in both replication samples. The rs12821256 SNP is located 350 kb upstream of KITLG, and Sulem et al. (2007) suggested that the SNP may affect expression of the KITLG gene or may be in linkage disequilibrium with another SNP that affects its expression. Sulem et al. (2007) found that the blond hair-associated rs12821256 C allele was found almost exclusively on an extended haplotype spanning a 400-kb region centered on the KITLG gene and found at frequencies of 80%, 63%, and 3% in the CEPH Utah (CEU), East Asian, and Nigerian Yoruba HapMap samples, respectively. Statistical methods indicated that the rs12821256 SNP is not itself under positive selection but rather is a 'hitchhiker' whose frequency is driven up by some selective advantage that is conferred by the extended haplotype.

Using a reporter gene with transgenic mice, Guenther et al. (2014) found that the region containing rs12821256 drove expression exclusively in hair follicles. Guenther et al. (2014) showed that rs12821256 overlapped a TCF/LEF (see LEF1, 153245) enhancer and that the variant G allele associated with blonde hair color reduced LEF binding in vitro. In transgenic mice, the G allele reduced Kitlg expression by approximately 20% and caused visibly lightened hair color compared with mice expressing the ancestral A allele. Guenther et al. (2014) concluded that rs12821256 is located within a distant regulatory enhancer for KITLG and influences hair color by reducing, but not eliminating, LEF binding.


.0002 SKIN/HAIR/EYE PIGMENTATION 7, DARK/LIGHT SKIN

KITLG, -326A-G, 5-PRIME UTR
  
RCV000013660

Miller et al. (2007) studied the rs642742 SNP, located 326 kb upstream of the KITLG transcription start site, to evaluate the role of the KITLG gene in human skin pigmentation (611664). The frequency of the ancestral A allele is at least 92% in West Africans, whereas the frequency of the derived G allele is at least 86% in Europeans and East Asians. Admixture mapping suggested that replacement of 2 West African alleles (AA) with 2 European alleles (GG) may account for a lightening of a person's skin by 6 to 7 melanin units. In comparison, the overall skin reflectance difference between West Africans and Europeans is 30 melanin units.


.0003 HYPERPIGMENTATION WITH OR WITHOUT HYPOPIGMENTATION, FAMILIAL PROGRESSIVE

KITLG, ASN36SER
  
RCV000013661

In a 6-generation Chinese family with familial progressive hyperpigmentation without hypopigmentation (FPHH; 145250), Wang et al. (2009) identified a c.107A-G transition in exon 2 of the KITLG gene, resulting in an asn36-to-ser (N36S) substitution. The mutation, which segregated with the disorder in the family, was not detected in 296 healthy unrelated Chinese individuals. This mutation results in a gain of function.

In affected members of 2 German families with familial progressive hyperpigmentation and hypopigmentation, originally reported by Zanardo et al. (2004), Amyere et al. (2011) identified heterozygosity for the N36S substitution, located at a highly conserved residue in the third beta strand of the KITLG gene. The mutation segregated with disease in both families.


.0004 HYPERPIGMENTATION WITH OR WITHOUT HYPOPIGMENTATION, FAMILIAL PROGRESSIVE

KITLG, VAL33ALA
  
RCV000162036

In affected individuals from a family of French Canadian ancestry with familial progressive hyper- and hypopigmentation (FPHH; 145250), originally reported by Hoo and Shrimpton (2005), Amyere et al. (2011) identified heterozygosity for a c.98T-C transition in the KITLG gene, resulting in a val33-to-ala (V33A) substitution at a highly conserved residue in the third beta strand. The mutation segregated with disease in the family.


.0005 HYPERPIGMENTATION WITH OR WITHOUT HYPOPIGMENTATION, FAMILIAL PROGRESSIVE

KITLG, THR34PRO
  
RCV000162037

In affected members of a Danish family with familial progressive hyper- and hypopigmentation (FPHH; 145250), Amyere et al. (2011) identified heterozygosity for a c.100A-C transversion in the KITLG gene, resulting in a thr34-to-pro (T34P) substitution at a highly conserved residue in the third beta strand. The mutation segregated with disease in the family. An affected 11-year-old boy exhibited general hyperpigmentation, accentuated on the neck, with scattered cafe-au-lait macules, lentigines, and small hypopigmented spots. His 43-year-old affected father had a large dark brown macule, surrounded by a rim of vitiligo, on the inner aspect of the left knee.


.0006 DEAFNESS, AUTOSOMAL DOMINANT 69

KITLG, 18-BP DEL/1-BP INS, NT286
  
RCV000203239

In 9 affected members of a large 5-generation Dutch family segregating autosomal dominant nonsyndromic congenital sensorineural unilateral or asymmetric hearing loss (DFNA69; 616697), Zazo Seco et al. (2015) identified heterozygosity for an 18-bp deletion and a 1-bp insertion (c.286_303delinsT, NM_000899.4), occurring in cis in exon 4 of the KITLG gene and causing a frameshift predicted to result in a ser96-to-ter (S96X) substitution. The mutation showed reduced penetrance, as it was present in 4 unaffected obligate carriers as well as in 1 additional unaffected individual and another with unknown disease status (calculated penetrance rate, 60 to 67%). The mutation was not found in 153 ethnically matched controls or in the Exome Variant Server, Nijmegen WES, ExAC, CIBERER Exome Server, or Baylor-Hopkins Center for Mendelian Genomics databases. Analysis of secreted KITLG in transfected NIH 3T3 cells detected no soluble S96X KITLG. In Western blot analysis of peripheral blood, there was no clear difference in patient KITLG levels compared to controls; the truncated S96X mutant was not detected, suggesting instability and/or degradation by nonsense-mediated decay.


.0007 DEAFNESS, AUTOSOMAL DOMINANT 69

KITLG, 3-BP DEL, 200ATT
  
RCV000203244

In a Spanish father and son with nonsyndromic congenital asymmetric sensorineural hearing loss (DFNA69; 616697), Zazo Seco et al. (2015) identified heterozygosity for a 3-bp in-frame deletion (c.200_202delATT, NM_000899.4) in exon 4 of the KITLG gene, resulting in a His67_Cys68delinsArg substitution. Western blot analysis of peripheral blood showed no clear difference in patient KITLG levels compared to controls. WGA staining of transfected NIH 3T3 cells indicated that the mutant protein fails to reach the cell membrane, and analysis of secreted KITLG in transfected NIH 3T3 cells did not detect mutant soluble KITLG.


.0008 VARIANT OF UNKNOWN SIGNIFICANCE

KITLG, LEU104VAL
  
RCV000203232

This variant is classified as a variant of unknown significance because its contribution to type 2 Waardenburg syndrome (WS2; see 193510) has not been confirmed.

Zazo Seco et al. (2015) screened a cohort of 64 Dutch probands with a clinical suspicion of WS2 for mutation in the KITLG gene and identified 1 proband with a heterozygous c.310C-G transversion (c.310C-G, NM_000899.4) in exon 4, resulting in a leu104-to-val (L104V) substitution at a highly conserved residue. The proband was a 5-year-old Dutch boy with unilateral deafness, heterochromia iridis, 1 hypopigmented macule on his thorax and 1 on his upper arm, and 1 hyperpigmented macule on his back. His mother, who was also heterozygous for the L104V variant, had normal hearing and skin, but exhibited small blue spots in the iris that were suggestive of heterochromia iridis. The mutation was not found in the Exome Variant Server, Nijmegen WES, ExAC, CIBERER Exome Server, or Baylor-Hopkins Center for Mendelian Genomics databases, which include at least 4,000 exomes of individuals of Dutch origin. Western blot analysis of peripheral blood showed no clear difference in patient KITLG levels compared to controls. Transfection studies in NIH 3T3 cells demonstrated that both wildtype and the L104V mutant KITLG were present in the cytoplasm and at the cell membrane, as well as in lamellipodia and filopodia. Analysis of secreted KITLG in transfected NIH 3T3 cells showed significant reduction of mutant soluble KITLG compared to wildtype soluble KITLG. The authors suggested that L104V variant might have a dominant-negative or gain-of-function effect.


.0009 WAARDENBURG SYNDROME, TYPE 2F

KITLG, ARG32CYS
  
RCV002260949

In a 16-year-old boy of Filipino ancestry with Waardenburg syndrome type 2F (WS2F; 619947), Ogawa et al. (2017) identified homozygosity for a c.94C-T transition in the KITLG gene, resulting in an arg32-to-cys (R32C) substitution adjacent to the VTNN motif. His mother and half-sister were heterozygous for the mutation, which was not found in the dbSNP, 1000 Genomes Project, or ExAC databases; DNA was unavailable from the father. The patient had congenital sensorineural hearing loss, brilliant blue irises, and depigmentation of the lower extremities. The authors noted that despite the homozygous nature of the proband's mutation, his pigmentary anomaly was somewhat milder than that observed in most cases of FPHH (145250), caused by heterozygous mutation in the KITLG gene.

In a 5-year-old Iranian boy (patient 1) and a 5-year-old Turkish girl (patient 3) with deafness, heterochromia iridis, and hypopigmentation of the skin, Vona et al. (2022) identified homozygosity for the c.94C-T transition (c.94C-T, NM_000889.4) in exon 2 of the KITLG gene, resulting in the R32C substitution within the signal peptide domain. The unaffected consanguineous parents in both families were heterozygous for the R32C variant, which was not found in an in-house database of more than 25,000 exomes, the Greater Middle Eastern Variome, the Iranome, or the gnomAD database v.2.1.1, but was present in gnomAD v.3.1.1 at very low minor allele frequency (1/152,098 alleles).


.0010 WAARDENBURG SYNDROME, TYPE 2F

KITLG, ILE148THR
  
RCV002260950

In a 2-year-old Southeast Asian girl (patient 2) with Waardenburg syndrome type 2F (WS2F; 619947), Vona et al. (2022) identified homozygosity for a c.443T-C transition (c.443T-C, NM_000889.4) in exon 5 of the KITLG gene, resulting in an ile148-to-thr (I148T) substitution within the KIT ligand domain. The patient had sensorineural hearing loss, hypomelanosis of skin and hair, including a white forelock, and blue irises. Her unaffected consanguineous parents were heterozygous for the variant, which was not found in an in-house database of more than 25,000 exomes, the Greater Middle Eastern Variome, the Iranome, or the gnomAD database v.3.1.1, but was present in gnomAD v.2.1.1 at very low minor allele frequency (1/249,924 alleles).


.0011 WAARDENBURG SYNDROME, TYPE 2F

KITLG, 2-BP DEL, 550AT
  
RCV002260951

In a 7-year-old Turkish girl (patient 5) with Waardenburg syndrome type 2F (WS2F; 619947), Vona et al. (2022) identified homozygosity for a 2-bp deletion (c.550_551del, NM_000889.4) in exon 6 of the KITLG gene, causing a frameshift predicted to result in a premature termination codon (Met184ValfsTer10) within the soluble KIT ligand domain. She had sensorineural hearing loss and generalized hypomelanosis of skin and hair, including a white forelock, but brown irises. Her unaffected second-cousin parents were heterozygous for the deletion, which was not found in an in-house database of more than 25,000 exomes, the Greater Middle Eastern Variome, the Iranome, or the gnomAD database v.2.1.1, but was present in gnomAD v.3.1.1 at very low minor allele frequency (1/151,736 alleles).


REFERENCES

  1. Amyere, M., Vogt, T., Hoo, J., Brandrup, F., Bygum, A., Boon, L., Vikkula, M. KITLG mutations cause familial progressive hyper- and hypopigmentation. J. Invest. Derm. 131: 1234-1239, 2011. [PubMed: 21368769, related citations] [Full Text]

  2. Brannan, C. I., Lyman, S. D., Williams, D. E., Eisenman, J., Anderson, D. M., Cosman, D., Bedell, M. A., Jenkins, N. A., Copeland, N. G. Steel-Dickie mutation encodes a c-kit ligand lacking transmembrane and cytoplasmic domains. Proc. Nat. Acad. Sci. 88: 4671-4674, 1991. [PubMed: 1711207, related citations] [Full Text]

  3. Ding, L., Saunders, T. L., Enikolopov, G., Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481: 457-462, 2012. [PubMed: 22281595, images, related citations] [Full Text]

  4. Geissler, E. N., Liao, M., Brook, J. D., Martin, F. H., Zsebo, K. M., Housman, D. E., Galli, S. J. Stem cell factor (SCF), a novel hematopoietic growth factor and ligand for c-kit tyrosine kinase receptor, maps on human chromosome 12 between 12q14.3 and 12qter. Somat. Cell Molec. Genet. 17: 207-214, 1991. [PubMed: 1707188, related citations] [Full Text]

  5. Guenther, C. A., Tasic, B., Luo, L., Bedell, M. A., Kingsley, D. M. A molecular basis for classic blond hair color in Europeans. Nature Genet. 46: 748-752, 2014. [PubMed: 24880339, images, related citations] [Full Text]

  6. Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., Hackett, N. R., Crystal, R. G., Besmer, P., Lyden, D., Moore, M. A. S., Werb, Z., Rafii, S. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of Kit-ligand. Cell 109: 625-637, 2002. [PubMed: 12062105, images, related citations] [Full Text]

  7. Hoo, J. J., Shrimpton, A. E. Familial hyper- and hypopigmentation with age-related pattern change. (Letter) Am. J. Med. Genet. 132A: 215-218, 2005. [PubMed: 15551335, related citations] [Full Text]

  8. Huang, E. J., Nocka, K. H., Buck, J., Besmer, P. Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2. Molec. Biol. Cell 3: 349-362, 1992. [PubMed: 1378327, related citations] [Full Text]

  9. Inra, C. N., Zhou, B. O., Acar, M., Murphy, M. M., Richardson, J., Zhao, Z., Morrison, S. J. A perisinusoidal niche for extramedullary haematopoiesis in the spleen. Nature 527: 466-471, 2015. [PubMed: 26570997, images, related citations] [Full Text]

  10. Liao, C.-P., Booker, R. C., Morrison, S. J., Le, L. Q. Identification of hair shaft progenitors that create a niche for hair pigmentation. Genes Dev. 31: 744-756, 2017. [PubMed: 28465357, images, related citations] [Full Text]

  11. Martin, F. H., Suggs, S. V., Langley, K. E., Lu, H. S., Ting, J., Okino, K. H., Morris, C. F., McNiece, I. K., Jacobsen, F. W., Mendiaz, E. A., Birkett, N. C., Smith, K. A., and 15 others. Primary structure and functional expression of rat and human stem cell factor DNAs. Cell 63: 203-211, 1990. [PubMed: 2208279, related citations] [Full Text]

  12. Mathew, S., Murty, V. V. V. S., Hunziker, W., Chaganti, R. S. K. Subregional mapping of 13 single-copy genes on the long arm of chromosome 12 by fluorescence in situ hybridization. Genomics 14: 775-779, 1992. [PubMed: 1427906, related citations] [Full Text]

  13. Matsuzawa, S., Sakashita, K., Kinoshita, T., Ito, S., Yamashita, T., Koike, K. IL-9 enhances the growth of human mast cell progenitors under stimulation with stem cell factor. J. Immun. 170: 3461-3467, 2003. [PubMed: 12646606, related citations] [Full Text]

  14. Miller, C. T., Beleza, S., Pollen, A. A., Schluter, D., Kittles, R. A., Shriver, M. D., Kingsley, D. M. cis-regulatory changes in Kit ligand expression and parallel evolution of pigmentation in sticklebacks and humans. Cell 131: 1179-1189, 2007. [PubMed: 18083106, images, related citations] [Full Text]

  15. Ogawa, Y., Kono, M., Akiyama, M. Pigmented macules in Waardenburg syndrome type 2 due to KITLG mutation. Pigment Cell Melanoma Res. 30: 501-504, 2017. [PubMed: 28504826, related citations] [Full Text]

  16. Rothschild, G., Sottas, C. M., Kissel, H., Agosti, V., Manova, K., Hardy, M. P., Besmer, P. A role for Kit receptor signaling in Leydig cell steroidogenesis. Biol. Reprod. 69: 925-932, 2003. [PubMed: 12773427, related citations] [Full Text]

  17. Shimizu, A., Sakai, Y., Ohno, K., Masaki, S., Kuwano, R., Takahashi, Y., Miyashita, N., Watanabe, T. A molecular genetic linkage map of mouse chromosome 10, including the Myb, S100b, Pah, Sl, and Ifg genes. Biochem. Genet. 30: 529-535, 1992. [PubMed: 1359872, related citations] [Full Text]

  18. Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., Jakobsdottir, M., Steinberg, S., and 13 others. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature Genet. 39: 1443-1452, 2007. [PubMed: 17952075, related citations] [Full Text]

  19. Vincent, S., Segretain, D., Nishikawa, S., Nishikawa, S., Sage, J., Cuzin, F., Rassoulzadegan, M. Stage-specific expression of the Kit receptor and its ligand (KL) during male gametogenesis in the mouse: a Kit-KL interaction critical for meiosis. Development 125: 4585-4593, 1998. [PubMed: 9778516, related citations] [Full Text]

  20. Vona, B., Schwartzbaum, D. A., Rodriguez, A. A., Lewis, S. S., Toosi, M. B., Radhakrishnan, P., Bozan, N., Akin, R., Doosti, M., Manju, R., Duman, D., Sineni, C. J., Nampoothiri, S., Karimiani, E. G., Houlden, H., Bademci, G., Tekin, M., Girisha, K. M., Maroofian, R., Douzgou, S. Biallelic KITLG variants lead to a distinct spectrum of hypomelanosis and sensorineural hearing loss. J. Europ. Acad. Derm. Venereol. 36: 1606-1611, 2022. [PubMed: 35543077, related citations] [Full Text]

  21. Wang, Z.-Q., Si, L., Tang, Q., Lin, D., Fu, Z., Zhang, J., Cui, B., Zhu, Y., Kong, X., Deng, M., Xia, Y., Xu, H., Le, W., Hu, L., Kong, X. Gain-of-function mutation of KIT ligand on melanin synthesis causes familial progressive hyperpigmentation. Am. J. Hum. Genet. 84: 672-677, 2009. [PubMed: 19375057, images, related citations] [Full Text]

  22. Zanardo, L., Stolz, W., Schmitz, G., Kaminski, W., Vikkula, M., Landthaler, M., Vogt, T. Progressive hyperpigmentation and generalized lentiginosis without associated systemic symptoms: a rare hereditary pigmentation disorder in south-east Germany. Acta Derm. Venereol. 84: 57-60, 2004. [PubMed: 15040480, related citations] [Full Text]

  23. Zazo Seco, C., Serrao de Castro, L., van Nierop, J. W., Morin, M., Jhangiani, S., Verver, E. J. J., Schraders, M., Maiwald, N., Wesdorp, M., Venselaar, H., Spruijt, L., Oostrik, J., and 20 others. Allelic mutations of KITLG, encoding KIT ligand, cause asymmetric and unilateral hearing loss and Waardenburg syndrome type 2. Am. J. Hum. Genet. 97: 647-660, 2015. [PubMed: 26522471, images, related citations] [Full Text]


Bao Lige - updated : 08/01/2022
Marla J. F. O'Neill - updated : 07/05/2022
Patricia A. Hartz - updated : 02/15/2018
Ada Hamosh - updated : 1/19/2016
Marla J. F. O'Neill - updated : 2/24/2015
Ada Hamosh - updated : 2/8/2012
Marla J. F. O'Neill - updated : 8/3/2011
Ada Hamosh - updated : 10/6/2009
Matthew B. Gross - updated : 8/3/2009
Patricia A. Hartz - updated : 8/3/2009
Paul J. Converse - updated : 3/13/2008
Anne M. Stumpf - updated : 1/16/2008
Victor A. McKusick - updated : 12/28/2007
Paul J. Converse - updated : 1/10/2006
Stylianos E. Antonarakis - updated : 9/24/2002
Anne M. Lopez - updated : 12/22/1998
Creation Date:
Victor A. McKusick : 5/15/1991
alopez : 08/29/2022
alopez : 08/01/2022
alopez : 07/05/2022
alopez : 08/06/2021
alopez : 05/15/2019
mgross : 02/15/2018
carol : 08/31/2016
carol : 05/27/2016
alopez : 1/19/2016
alopez : 12/29/2015
carol : 5/7/2015
carol : 2/26/2015
carol : 2/26/2015
mcolton : 2/24/2015
alopez : 2/10/2012
terry : 2/8/2012
carol : 9/20/2011
wwang : 8/5/2011
terry : 8/3/2011
alopez : 10/15/2009
terry : 10/6/2009
mgross : 8/3/2009
terry : 8/3/2009
mgross : 3/17/2008
mgross : 3/14/2008
terry : 3/13/2008
alopez : 1/17/2008
alopez : 1/16/2008
terry : 12/28/2007
mgross : 1/10/2006
mgross : 9/24/2002
joanna : 6/19/2000
alopez : 6/19/2000
terry : 1/15/1999
carol : 12/22/1998
alopez : 12/22/1998
alopez : 9/4/1998
carol : 2/1/1993
carol : 1/29/1993
carol : 1/5/1993
carol : 12/14/1992
supermim : 3/16/1992
carol : 3/2/1992

* 184745

KIT LIGAND; KITLG


Alternative titles; symbols

KL; KITL
MAST CELL GROWTH FACTOR; MGF
MGF STEM CELL FACTOR; SCF
STEEL, MOUSE, HOMOLOG OF
STEEL FACTOR; SF


HGNC Approved Gene Symbol: KITLG

SNOMEDCT: 715630006;  


Cytogenetic location: 12q21.32     Genomic coordinates (GRCh38): 12:88,492,793-88,580,471 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12q21.32 [Skin/hair/eye pigmentation 7, blond/brown hair] 611664 3
Deafness, autosomal dominant 69, unilateral or asymmetric 616697 Autosomal dominant 3
Hyperpigmentation with or without hypopigmentation 145250 Autosomal dominant 3
Waardenburg syndrome, type 2F 619947 Autosomal recessive 3

TEXT

Description

KITLG and its receptor, KIT (164920), function in hematopoiesis, melanogenesis, and gametogenesis (Rothschild et al., 2003).


Cloning and Expression

Stem cell factor is a hematopoietic growth factor and ligand for the KIT tyrosine kinase receptor. In the mouse, this growth factor is encoded by Sl ('steel'), a gene critical to the development of several distinct cell lineages during embryonic life as well as having important effects on hematopoiesis in the adult animal. Steel factor (SF) is a synonym for stem cell factor. The steel-Dickie mutation in the mouse, symbolized Sl(d), was shown by Brannan et al. (1991) to consist of a 4-kb intragenic deletion in mast cell growth factor (MGF) genomic sequences. As a consequence of the deletion, a soluble truncated growth factor was formed that lacked both transmembrane and cytoplasmic domains. The results provided direct evidence that Sl encodes MGF.

Using probes based on the sequence of rat Scf, Martin et al. (1990) isolated cDNA and genomic clones of human SCF. The deduced 248-amino acid human protein has an N-terminal signal sequence, a predicted transmembrane domain near the C terminus, and 5 predicted N-glycosylation sites. Northern blot analysis detected a 6-kb SCF transcript in a human fibrosarcoma cell line.

Huang et al. (1992) cloned full-length mouse Kitl, which they called Kl1, and a Kitl splice variant, which they called Kl2. Kl2 encodes an isoform lacking a 28-amino acid sequence preceding the transmembrane region of Kl1. RT-PCR and RNase protection assays revealed tissue-specific expression patterns for both Kl1 and Kl2. Using transfected COS-1 cells, Huang et al. (1992) showed that proteolytic cleavage of the Kl1 transmembrane precursor generated a soluble, biologically active form of Kl. Kl2 also produced a soluble, biologically active form of Kl, but with somewhat diminished efficiency. Proteolytic processing of both the Kl1 and Kl2 transmembrane proteins occurred on the cell surface.

Using RT-PCR, Zazo Seco et al. (2015) assessed transcription of Kitl in mouse cochlea and obtained 2 amplification products that corresponded to Kitl transcripts with and without exon 6. In addition, qPCR demonstrated that the relative levels of both Kitl alternative transcripts were higher at postnatal day 28 than at postnatal day 2. Zazo Seco et al. (2015) suggested that Kitl functions postnatally in the mouse inner ear.


Mapping

The Sl locus maps to the distal region of mouse chromosome 10 (Shimizu et al., 1992), in the vicinity of genes that have been mapped to human chromosome 12. On the basis of analysis of somatic cell hybrids between human cells and either hamster or mouse cells, Geissler et al. (1991) reported that the human gene maps to 12q14.3-qter. Mathew et al. (1992) regionalized the MGF gene to 12q22 by in situ hybridization.


Gene Function

Martin et al. (1990) found that SCF augmented the proliferation of both myeloid and lymphoid hematopoietic progenitors in bone marrow cultures.

Using Western blot and immunohistochemical analyses, Vincent et al. (1998) found that membrane-bound Kl2 was the major Kl isoform expressed in mouse testis and on mouse Sertoli cells. At stages VII to VIII, when spermatocytes enter meiosis, Kl2 was expressed on Sertoli cells from the peripheral to the adluminal compartment of the tubule. Kit was also expressed on the surface of germ cells up to the pachytene stage. Blocking interaction of Kl2 with Kit via blocking antibody or treatment with soluble Kl protein inhibited the appearance of haploid cells and completion of meiosis.

Rothschild et al. (2003) found that steroidogenesis in mouse Leydig cells was dependent on Kitl signaling and involved phosphoinositide 3-kinase (PI3K). Leydig cells of mice expressing mutant Kit unable to bind the p85 subunit of PI3K (PIK3R1; 171833) were unable to respond effectively to Kitl stimulation; however, mutant animals had normal serum testosterone levels. The findings suggested a model in which the mutant Leydig cells initially produce lower levels of testosterone, reducing testosterone negative feedback on the hypothalamic-pituitary axis, which leads to elevated luteinizing hormone (LH; see 152780) secretion and restoration of normal serum testosterone levels. Rothschild et al. (2003) concluded that KITL, acting via PI3K, is a paracrine regulator of Leydig cell steroidogenesis.

Matsuzawa et al. (2003) found that incubation of CD34 (142230)-positive/CD38 (107270)-positive cord blood cells with IL9 (146931) and SCF increased both the number and size of mast cell colonies compared with incubation of these cells with SCF alone. There was no difference in progeny generation between 6-week cultured mast cells incubated with IL9 and SCF and those incubated with SCF alone. IL9 and SCF increased mast cell colony numbers in peripheral blood cells, and did so more in cells from asthmatic patients than in cells from normal control children. Matsuzawa et al. (2003) concluded that IL9 is a potent enhancer of SCF-dependent growth of human mast cell progenitors.

Using Scf(gfp) knockin mice, Ding et al. (2012) found that SCF was primarily expressed by perivascular cells throughout the bone marrow. Hematopoietic stem cell (HSC) frequency and function were not affected when Scf was conditionally deleted from hematopoietic cells, osteoblasts, or nestin-cre- or nestin-creER-expressing cells. However, HSCs were depleted from bone marrow when Scf was deleted from endothelial cells or leptin receptor (LEPR; 601007)-expressing perivascular stromal cells. Most HSCs were lost when Scf was deleted from both endothelial and Lepr-expressing perivascular cells. Ding et al. (2012) concluded that HSCs reside in a perivascular niche in which multiple cell types express factors that promote HSC maintenance.

Inra et al. (2015) assessed the sources of the extramedullary hematopoiesis niche factors Scf and Cxcl12 (600835) in the mouse spleen after induction by myeloablation, blood loss, or pregnancy. In each case, Scf was expressed by endothelial cells and Tcf21 (603306)-positive stromal cells, primarily around sinusoids in the red pulp, while Cxcl12 was expressed by a subset of Tcf21-positive stromal cells. Extramedullary hematopoiesis induction markedly expanded the Scf-expressing endothelial cells and stromal cells by inducing proliferation. Most splenic HSCs were adjacent to Tcf21-positive stromal cells in red pulp. Conditional deletion of Scf from spleen endothelial cells, or of Scf or Cxcl12 from Tcf21-positive stromal cells, severely reduced spleen extramedullary hematopoiesis and reduced blood cell counts without affecting bone marrow hematopoiesis. Inra et al. (2015) concluded that endothelial cells and Tcf21-positive stromal cells thus create a perisinusoidal extramedullary hematopoiesis niche in the spleen, which is necessary for the physiologic response to diverse hematopoietic stresses.

Liao et al. (2017) found that mice with conditional deletion of Scf in Krox20 (129010) lineage cells exhibited progressive hair graying and lost all hair pigmentation early in life, suggesting that Krox20 lineage cells were the main source of Scf for follicular melanocytes to produce hair pigment. Depletion of Scf in epithelial cells of mice completely abolished hair pigmentation. Lacz reporter analysis suggested that hair pigmentation was regulated by Scf expression in hair shaft progenitor cells in the hair matrix. These hair shaft progenitors in the matrix were differentiated from follicular epithelial cells expressing Krox20. Liao et al. (2017) concluded that their study delineated the origin of SCF expression in hair matrix progenitors as a niche for follicular mature melanocytes and that their SCF is indispensible for hair pigmentation.


Molecular Genetics

Normal Skin/Hair/Eye Pigmentation Variation

Sulem et al. (2007) carried out a genomewide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun, and freckling among 2,986 Icelanders. The closely associated SNPs from 6 regions were replicated in a second sample of Icelanders and a sample of Dutch. The SNPs from all 6 regions met the criteria for genomewide significance. Sulem et al. (2007) found that a variant near KITLG (184745.0001) was associated with hair color (611664) in a genomewide association scan in Icelanders and Dutch.

Miller et al. (2007) investigated parallel origins in pigmentation changes in stickleback fish and humans. Using high-resolution mapping and expression experiments, they mapped light gills and ventrums in fish to a divergent regulatory allele of the Kitlg gene. European and East Asian humans also share derived alleles at the KITLG locus. For the rs642742 SNP (184745.0002), located 326 kb upstream of the KITLG transcription start site, the frequency of the ancestral A allele is at least 92% in West Africans, whereas the frequency of the derived G allele is at least 86% in Europeans and East Asians. Admixture mapping suggested that replacement of AA with GG in the rs642742 SNP may account for a lightening of a person's skin by 6 to 7 melanin units (see 611664). In comparison, the overall skin reflectance difference between West Africans and Europeans is 30 melanin units.

Familial Progressive Hyperpigmentation with or without Hypopigmentation

In a 6-generation Chinese family with progressive hyperpigmentation (FPHH; 145250), Wang et al. (2009) identified a missense mutation in the KITLG gene (N36S; 184745.0003). This mutation resulted in a gain of function and increased the content of melanin by 109% compared with wildtype KITLG in human melanoma cells. Consistent with this result, tyrosinase (606933) activity was significantly increased by the mutant compared with wildtype.

In affected individuals from 4 families with FPHH, Amyere et al. (2011) identified heterozygosity for missense mutations in the KITLG gene (184745.0003-184745.0005).

Deafness, Autosomal Dominant 69

In a large 5-generation Dutch family segregating autosomal dominant nonsyndromic hearing loss mapping to chromosome 12q21.32-q23.1 (DFNA69; 616697), Zazo Seco et al. (2015) identified a heterozygous frameshift mutation in the KITLG gene (184745.0006) that was present in all affected individuals. The mutation was also present in 4 unaffected obligate carriers, as well as 1 additional unaffected individual and another with unknown disease status, for a calculated penetrance rate of 60 to 67%. All evaluated family members had skin type I or II, blond hair, and blue eyes; hypo- or depigmentation of the skin was not observed in the younger generation, and changes seen in older generations appeared to be age-related and did not segregate with hearing loss. One affected individual who had hair and eye color lighter than other family members was also heterozygous for the G allele of SNP rs12821256 (184745.0001). Analysis of KITLG in a panel of 23 unrelated probands with autosomal dominant nonsyndromic unilateral or asymmetric hearing loss identified a Spanish father and son with an in-frame deletion in the KITLG gene (184745.0007), neither of whom exhibited hypo- or hyperpigmentation of the skin.

Waardenburg Syndrome, Type 2F

In a 16-year-old boy of Filipino ancestry with Waardenburg syndrome type 2F (WS2F; 619947) manifest as sensorineural deafness, brilliant blue irises, and hypopigmentation of the lower extremities, Ogawa et al. (2017) identified homozygosity for a missense mutation in the KITLG gene (R32C; 184745.0009) that segregated with disease in the family and was not found in public variant databases.

Using GeneMatcher, Vona et al. (2022) identified 6 unrelated children who had homozygous mutations in the KITLG gene (see, e.g., 184745.0009-184745.0011) and features consistent with WS2. All 6 probands had sensorineural hearing loss and pigmentary abnormalities of the hair and skin, and 5 also had pigmentary changes of the iris. Two of the probands were homozygous for the same R32C variant that had previously been reported in a Filipino boy with WS2 by Ogawa et al. (2017). The variants segregated with disease in the respective families and were either not found or were present at very low minor allele frequency in public variant databases.

Associations Pending Confirmation

A heterozygous variant in the KITLG gene (184745.0008) has been reported in a patient exhibiting features consistent with Waardenburg syndrome-2 (WS2; see 193510).

For discussion of a possible association between variation in the KITLG gene and testicular germ cell tumors, see 273300.


Animal Model

Matrix metalloproteinase-9 (MMP9; 120361), induced in bone marrow cells, releases soluble KITLG, permitting the transfer of endothelial and hematopoietic stem cells (HSCs) from the quiescent to proliferative niche. Heissig et al. (2002) found that bone marrow ablation in wildtype Mmp9 mice induced Sdf1 (600835), which upregulated Mmp9 expression and caused shedding of Kitl and recruitment of Kit-positive stem/progenitors. In Mmp9 -/- mice, release of Kitl and HSC motility were impaired, resulting in failure of hematopoietic recovery and increased mortality, while exogenous Kitl restored hematopoiesis and survival after bone marrow ablation. Release of Kitl by Mmp9 enabled bone marrow repopulating cells to translocate to a permissive vascular niche favoring differentiation and reconstitution of the stem/progenitor cell pool.


ALLELIC VARIANTS 11 Selected Examples):

.0001   SKIN/HAIR/EYE PIGMENTATION 7, BLOND/BROWN HAIR

KITLG, T-C ({dbSNP rs12821256})
SNP: rs12821256, gnomAD: rs12821256, ClinVar: RCV000013659

In a genomewide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun, and freckling in Icelandic and Dutch population samples, Sulem et al. (2007) found that the C allele of a single SNP on 12q21.33, rs12821256, showed genomewide significance in the initial scan for blond versus brown hair (OR = 2.32, P = 1.9 x 10(-14)) (611664). This association was confirmed in both replication samples. The rs12821256 SNP is located 350 kb upstream of KITLG, and Sulem et al. (2007) suggested that the SNP may affect expression of the KITLG gene or may be in linkage disequilibrium with another SNP that affects its expression. Sulem et al. (2007) found that the blond hair-associated rs12821256 C allele was found almost exclusively on an extended haplotype spanning a 400-kb region centered on the KITLG gene and found at frequencies of 80%, 63%, and 3% in the CEPH Utah (CEU), East Asian, and Nigerian Yoruba HapMap samples, respectively. Statistical methods indicated that the rs12821256 SNP is not itself under positive selection but rather is a 'hitchhiker' whose frequency is driven up by some selective advantage that is conferred by the extended haplotype.

Using a reporter gene with transgenic mice, Guenther et al. (2014) found that the region containing rs12821256 drove expression exclusively in hair follicles. Guenther et al. (2014) showed that rs12821256 overlapped a TCF/LEF (see LEF1, 153245) enhancer and that the variant G allele associated with blonde hair color reduced LEF binding in vitro. In transgenic mice, the G allele reduced Kitlg expression by approximately 20% and caused visibly lightened hair color compared with mice expressing the ancestral A allele. Guenther et al. (2014) concluded that rs12821256 is located within a distant regulatory enhancer for KITLG and influences hair color by reducing, but not eliminating, LEF binding.


.0002   SKIN/HAIR/EYE PIGMENTATION 7, DARK/LIGHT SKIN

KITLG, -326A-G, 5-PRIME UTR
SNP: rs642742, gnomAD: rs642742, ClinVar: RCV000013660

Miller et al. (2007) studied the rs642742 SNP, located 326 kb upstream of the KITLG transcription start site, to evaluate the role of the KITLG gene in human skin pigmentation (611664). The frequency of the ancestral A allele is at least 92% in West Africans, whereas the frequency of the derived G allele is at least 86% in Europeans and East Asians. Admixture mapping suggested that replacement of 2 West African alleles (AA) with 2 European alleles (GG) may account for a lightening of a person's skin by 6 to 7 melanin units. In comparison, the overall skin reflectance difference between West Africans and Europeans is 30 melanin units.


.0003   HYPERPIGMENTATION WITH OR WITHOUT HYPOPIGMENTATION, FAMILIAL PROGRESSIVE

KITLG, ASN36SER
SNP: rs121918653, ClinVar: RCV000013661

In a 6-generation Chinese family with familial progressive hyperpigmentation without hypopigmentation (FPHH; 145250), Wang et al. (2009) identified a c.107A-G transition in exon 2 of the KITLG gene, resulting in an asn36-to-ser (N36S) substitution. The mutation, which segregated with the disorder in the family, was not detected in 296 healthy unrelated Chinese individuals. This mutation results in a gain of function.

In affected members of 2 German families with familial progressive hyperpigmentation and hypopigmentation, originally reported by Zanardo et al. (2004), Amyere et al. (2011) identified heterozygosity for the N36S substitution, located at a highly conserved residue in the third beta strand of the KITLG gene. The mutation segregated with disease in both families.


.0004   HYPERPIGMENTATION WITH OR WITHOUT HYPOPIGMENTATION, FAMILIAL PROGRESSIVE

KITLG, VAL33ALA
SNP: rs730882156, ClinVar: RCV000162036

In affected individuals from a family of French Canadian ancestry with familial progressive hyper- and hypopigmentation (FPHH; 145250), originally reported by Hoo and Shrimpton (2005), Amyere et al. (2011) identified heterozygosity for a c.98T-C transition in the KITLG gene, resulting in a val33-to-ala (V33A) substitution at a highly conserved residue in the third beta strand. The mutation segregated with disease in the family.


.0005   HYPERPIGMENTATION WITH OR WITHOUT HYPOPIGMENTATION, FAMILIAL PROGRESSIVE

KITLG, THR34PRO
SNP: rs730882157, ClinVar: RCV000162037

In affected members of a Danish family with familial progressive hyper- and hypopigmentation (FPHH; 145250), Amyere et al. (2011) identified heterozygosity for a c.100A-C transversion in the KITLG gene, resulting in a thr34-to-pro (T34P) substitution at a highly conserved residue in the third beta strand. The mutation segregated with disease in the family. An affected 11-year-old boy exhibited general hyperpigmentation, accentuated on the neck, with scattered cafe-au-lait macules, lentigines, and small hypopigmented spots. His 43-year-old affected father had a large dark brown macule, surrounded by a rim of vitiligo, on the inner aspect of the left knee.


.0006   DEAFNESS, AUTOSOMAL DOMINANT 69

KITLG, 18-BP DEL/1-BP INS, NT286
SNP: rs864309653, ClinVar: RCV000203239

In 9 affected members of a large 5-generation Dutch family segregating autosomal dominant nonsyndromic congenital sensorineural unilateral or asymmetric hearing loss (DFNA69; 616697), Zazo Seco et al. (2015) identified heterozygosity for an 18-bp deletion and a 1-bp insertion (c.286_303delinsT, NM_000899.4), occurring in cis in exon 4 of the KITLG gene and causing a frameshift predicted to result in a ser96-to-ter (S96X) substitution. The mutation showed reduced penetrance, as it was present in 4 unaffected obligate carriers as well as in 1 additional unaffected individual and another with unknown disease status (calculated penetrance rate, 60 to 67%). The mutation was not found in 153 ethnically matched controls or in the Exome Variant Server, Nijmegen WES, ExAC, CIBERER Exome Server, or Baylor-Hopkins Center for Mendelian Genomics databases. Analysis of secreted KITLG in transfected NIH 3T3 cells detected no soluble S96X KITLG. In Western blot analysis of peripheral blood, there was no clear difference in patient KITLG levels compared to controls; the truncated S96X mutant was not detected, suggesting instability and/or degradation by nonsense-mediated decay.


.0007   DEAFNESS, AUTOSOMAL DOMINANT 69

KITLG, 3-BP DEL, 200ATT
SNP: rs864309654, ClinVar: RCV000203244

In a Spanish father and son with nonsyndromic congenital asymmetric sensorineural hearing loss (DFNA69; 616697), Zazo Seco et al. (2015) identified heterozygosity for a 3-bp in-frame deletion (c.200_202delATT, NM_000899.4) in exon 4 of the KITLG gene, resulting in a His67_Cys68delinsArg substitution. Western blot analysis of peripheral blood showed no clear difference in patient KITLG levels compared to controls. WGA staining of transfected NIH 3T3 cells indicated that the mutant protein fails to reach the cell membrane, and analysis of secreted KITLG in transfected NIH 3T3 cells did not detect mutant soluble KITLG.


.0008   VARIANT OF UNKNOWN SIGNIFICANCE

KITLG, LEU104VAL
SNP: rs864309655, ClinVar: RCV000203232

This variant is classified as a variant of unknown significance because its contribution to type 2 Waardenburg syndrome (WS2; see 193510) has not been confirmed.

Zazo Seco et al. (2015) screened a cohort of 64 Dutch probands with a clinical suspicion of WS2 for mutation in the KITLG gene and identified 1 proband with a heterozygous c.310C-G transversion (c.310C-G, NM_000899.4) in exon 4, resulting in a leu104-to-val (L104V) substitution at a highly conserved residue. The proband was a 5-year-old Dutch boy with unilateral deafness, heterochromia iridis, 1 hypopigmented macule on his thorax and 1 on his upper arm, and 1 hyperpigmented macule on his back. His mother, who was also heterozygous for the L104V variant, had normal hearing and skin, but exhibited small blue spots in the iris that were suggestive of heterochromia iridis. The mutation was not found in the Exome Variant Server, Nijmegen WES, ExAC, CIBERER Exome Server, or Baylor-Hopkins Center for Mendelian Genomics databases, which include at least 4,000 exomes of individuals of Dutch origin. Western blot analysis of peripheral blood showed no clear difference in patient KITLG levels compared to controls. Transfection studies in NIH 3T3 cells demonstrated that both wildtype and the L104V mutant KITLG were present in the cytoplasm and at the cell membrane, as well as in lamellipodia and filopodia. Analysis of secreted KITLG in transfected NIH 3T3 cells showed significant reduction of mutant soluble KITLG compared to wildtype soluble KITLG. The authors suggested that L104V variant might have a dominant-negative or gain-of-function effect.


.0009   WAARDENBURG SYNDROME, TYPE 2F

KITLG, ARG32CYS
SNP: rs1870699640, ClinVar: RCV002260949

In a 16-year-old boy of Filipino ancestry with Waardenburg syndrome type 2F (WS2F; 619947), Ogawa et al. (2017) identified homozygosity for a c.94C-T transition in the KITLG gene, resulting in an arg32-to-cys (R32C) substitution adjacent to the VTNN motif. His mother and half-sister were heterozygous for the mutation, which was not found in the dbSNP, 1000 Genomes Project, or ExAC databases; DNA was unavailable from the father. The patient had congenital sensorineural hearing loss, brilliant blue irises, and depigmentation of the lower extremities. The authors noted that despite the homozygous nature of the proband's mutation, his pigmentary anomaly was somewhat milder than that observed in most cases of FPHH (145250), caused by heterozygous mutation in the KITLG gene.

In a 5-year-old Iranian boy (patient 1) and a 5-year-old Turkish girl (patient 3) with deafness, heterochromia iridis, and hypopigmentation of the skin, Vona et al. (2022) identified homozygosity for the c.94C-T transition (c.94C-T, NM_000889.4) in exon 2 of the KITLG gene, resulting in the R32C substitution within the signal peptide domain. The unaffected consanguineous parents in both families were heterozygous for the R32C variant, which was not found in an in-house database of more than 25,000 exomes, the Greater Middle Eastern Variome, the Iranome, or the gnomAD database v.2.1.1, but was present in gnomAD v.3.1.1 at very low minor allele frequency (1/152,098 alleles).


.0010   WAARDENBURG SYNDROME, TYPE 2F

KITLG, ILE148THR
SNP: rs751013211, gnomAD: rs751013211, ClinVar: RCV002260950

In a 2-year-old Southeast Asian girl (patient 2) with Waardenburg syndrome type 2F (WS2F; 619947), Vona et al. (2022) identified homozygosity for a c.443T-C transition (c.443T-C, NM_000889.4) in exon 5 of the KITLG gene, resulting in an ile148-to-thr (I148T) substitution within the KIT ligand domain. The patient had sensorineural hearing loss, hypomelanosis of skin and hair, including a white forelock, and blue irises. Her unaffected consanguineous parents were heterozygous for the variant, which was not found in an in-house database of more than 25,000 exomes, the Greater Middle Eastern Variome, the Iranome, or the gnomAD database v.3.1.1, but was present in gnomAD v.2.1.1 at very low minor allele frequency (1/249,924 alleles).


.0011   WAARDENBURG SYNDROME, TYPE 2F

KITLG, 2-BP DEL, 550AT
SNP: rs1404903521, ClinVar: RCV002260951

In a 7-year-old Turkish girl (patient 5) with Waardenburg syndrome type 2F (WS2F; 619947), Vona et al. (2022) identified homozygosity for a 2-bp deletion (c.550_551del, NM_000889.4) in exon 6 of the KITLG gene, causing a frameshift predicted to result in a premature termination codon (Met184ValfsTer10) within the soluble KIT ligand domain. She had sensorineural hearing loss and generalized hypomelanosis of skin and hair, including a white forelock, but brown irises. Her unaffected second-cousin parents were heterozygous for the deletion, which was not found in an in-house database of more than 25,000 exomes, the Greater Middle Eastern Variome, the Iranome, or the gnomAD database v.2.1.1, but was present in gnomAD v.3.1.1 at very low minor allele frequency (1/151,736 alleles).


REFERENCES

  1. Amyere, M., Vogt, T., Hoo, J., Brandrup, F., Bygum, A., Boon, L., Vikkula, M. KITLG mutations cause familial progressive hyper- and hypopigmentation. J. Invest. Derm. 131: 1234-1239, 2011. [PubMed: 21368769] [Full Text: https://doi.org/10.1038/jid.2011.29]

  2. Brannan, C. I., Lyman, S. D., Williams, D. E., Eisenman, J., Anderson, D. M., Cosman, D., Bedell, M. A., Jenkins, N. A., Copeland, N. G. Steel-Dickie mutation encodes a c-kit ligand lacking transmembrane and cytoplasmic domains. Proc. Nat. Acad. Sci. 88: 4671-4674, 1991. [PubMed: 1711207] [Full Text: https://doi.org/10.1073/pnas.88.11.4671]

  3. Ding, L., Saunders, T. L., Enikolopov, G., Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481: 457-462, 2012. [PubMed: 22281595] [Full Text: https://doi.org/10.1038/nature10783]

  4. Geissler, E. N., Liao, M., Brook, J. D., Martin, F. H., Zsebo, K. M., Housman, D. E., Galli, S. J. Stem cell factor (SCF), a novel hematopoietic growth factor and ligand for c-kit tyrosine kinase receptor, maps on human chromosome 12 between 12q14.3 and 12qter. Somat. Cell Molec. Genet. 17: 207-214, 1991. [PubMed: 1707188] [Full Text: https://doi.org/10.1007/BF01232978]

  5. Guenther, C. A., Tasic, B., Luo, L., Bedell, M. A., Kingsley, D. M. A molecular basis for classic blond hair color in Europeans. Nature Genet. 46: 748-752, 2014. [PubMed: 24880339] [Full Text: https://doi.org/10.1038/ng.2991]

  6. Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., Hackett, N. R., Crystal, R. G., Besmer, P., Lyden, D., Moore, M. A. S., Werb, Z., Rafii, S. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of Kit-ligand. Cell 109: 625-637, 2002. [PubMed: 12062105] [Full Text: https://doi.org/10.1016/s0092-8674(02)00754-7]

  7. Hoo, J. J., Shrimpton, A. E. Familial hyper- and hypopigmentation with age-related pattern change. (Letter) Am. J. Med. Genet. 132A: 215-218, 2005. [PubMed: 15551335] [Full Text: https://doi.org/10.1002/ajmg.a.30381]

  8. Huang, E. J., Nocka, K. H., Buck, J., Besmer, P. Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2. Molec. Biol. Cell 3: 349-362, 1992. [PubMed: 1378327] [Full Text: https://doi.org/10.1091/mbc.3.3.349]

  9. Inra, C. N., Zhou, B. O., Acar, M., Murphy, M. M., Richardson, J., Zhao, Z., Morrison, S. J. A perisinusoidal niche for extramedullary haematopoiesis in the spleen. Nature 527: 466-471, 2015. [PubMed: 26570997] [Full Text: https://doi.org/10.1038/nature15530]

  10. Liao, C.-P., Booker, R. C., Morrison, S. J., Le, L. Q. Identification of hair shaft progenitors that create a niche for hair pigmentation. Genes Dev. 31: 744-756, 2017. [PubMed: 28465357] [Full Text: https://doi.org/10.1101/gad.298703.117]

  11. Martin, F. H., Suggs, S. V., Langley, K. E., Lu, H. S., Ting, J., Okino, K. H., Morris, C. F., McNiece, I. K., Jacobsen, F. W., Mendiaz, E. A., Birkett, N. C., Smith, K. A., and 15 others. Primary structure and functional expression of rat and human stem cell factor DNAs. Cell 63: 203-211, 1990. [PubMed: 2208279] [Full Text: https://doi.org/10.1016/0092-8674(90)90301-t]

  12. Mathew, S., Murty, V. V. V. S., Hunziker, W., Chaganti, R. S. K. Subregional mapping of 13 single-copy genes on the long arm of chromosome 12 by fluorescence in situ hybridization. Genomics 14: 775-779, 1992. [PubMed: 1427906] [Full Text: https://doi.org/10.1016/s0888-7543(05)80184-3]

  13. Matsuzawa, S., Sakashita, K., Kinoshita, T., Ito, S., Yamashita, T., Koike, K. IL-9 enhances the growth of human mast cell progenitors under stimulation with stem cell factor. J. Immun. 170: 3461-3467, 2003. [PubMed: 12646606] [Full Text: https://doi.org/10.4049/jimmunol.170.7.3461]

  14. Miller, C. T., Beleza, S., Pollen, A. A., Schluter, D., Kittles, R. A., Shriver, M. D., Kingsley, D. M. cis-regulatory changes in Kit ligand expression and parallel evolution of pigmentation in sticklebacks and humans. Cell 131: 1179-1189, 2007. [PubMed: 18083106] [Full Text: https://doi.org/10.1016/j.cell.2007.10.055]

  15. Ogawa, Y., Kono, M., Akiyama, M. Pigmented macules in Waardenburg syndrome type 2 due to KITLG mutation. Pigment Cell Melanoma Res. 30: 501-504, 2017. [PubMed: 28504826] [Full Text: https://doi.org/10.1111/pcmr.12597]

  16. Rothschild, G., Sottas, C. M., Kissel, H., Agosti, V., Manova, K., Hardy, M. P., Besmer, P. A role for Kit receptor signaling in Leydig cell steroidogenesis. Biol. Reprod. 69: 925-932, 2003. [PubMed: 12773427] [Full Text: https://doi.org/10.1095/biolreprod.102.014548]

  17. Shimizu, A., Sakai, Y., Ohno, K., Masaki, S., Kuwano, R., Takahashi, Y., Miyashita, N., Watanabe, T. A molecular genetic linkage map of mouse chromosome 10, including the Myb, S100b, Pah, Sl, and Ifg genes. Biochem. Genet. 30: 529-535, 1992. [PubMed: 1359872] [Full Text: https://doi.org/10.1007/BF01037591]

  18. Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., Jakobsdottir, M., Steinberg, S., and 13 others. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature Genet. 39: 1443-1452, 2007. [PubMed: 17952075] [Full Text: https://doi.org/10.1038/ng.2007.13]

  19. Vincent, S., Segretain, D., Nishikawa, S., Nishikawa, S., Sage, J., Cuzin, F., Rassoulzadegan, M. Stage-specific expression of the Kit receptor and its ligand (KL) during male gametogenesis in the mouse: a Kit-KL interaction critical for meiosis. Development 125: 4585-4593, 1998. [PubMed: 9778516] [Full Text: https://doi.org/10.1242/dev.125.22.4585]

  20. Vona, B., Schwartzbaum, D. A., Rodriguez, A. A., Lewis, S. S., Toosi, M. B., Radhakrishnan, P., Bozan, N., Akin, R., Doosti, M., Manju, R., Duman, D., Sineni, C. J., Nampoothiri, S., Karimiani, E. G., Houlden, H., Bademci, G., Tekin, M., Girisha, K. M., Maroofian, R., Douzgou, S. Biallelic KITLG variants lead to a distinct spectrum of hypomelanosis and sensorineural hearing loss. J. Europ. Acad. Derm. Venereol. 36: 1606-1611, 2022. [PubMed: 35543077] [Full Text: https://doi.org/10.1111/jdv.18207]

  21. Wang, Z.-Q., Si, L., Tang, Q., Lin, D., Fu, Z., Zhang, J., Cui, B., Zhu, Y., Kong, X., Deng, M., Xia, Y., Xu, H., Le, W., Hu, L., Kong, X. Gain-of-function mutation of KIT ligand on melanin synthesis causes familial progressive hyperpigmentation. Am. J. Hum. Genet. 84: 672-677, 2009. [PubMed: 19375057] [Full Text: https://doi.org/10.1016/j.ajhg.2009.03.019]

  22. Zanardo, L., Stolz, W., Schmitz, G., Kaminski, W., Vikkula, M., Landthaler, M., Vogt, T. Progressive hyperpigmentation and generalized lentiginosis without associated systemic symptoms: a rare hereditary pigmentation disorder in south-east Germany. Acta Derm. Venereol. 84: 57-60, 2004. [PubMed: 15040480] [Full Text: https://doi.org/10.1080/00015550310005780]

  23. Zazo Seco, C., Serrao de Castro, L., van Nierop, J. W., Morin, M., Jhangiani, S., Verver, E. J. J., Schraders, M., Maiwald, N., Wesdorp, M., Venselaar, H., Spruijt, L., Oostrik, J., and 20 others. Allelic mutations of KITLG, encoding KIT ligand, cause asymmetric and unilateral hearing loss and Waardenburg syndrome type 2. Am. J. Hum. Genet. 97: 647-660, 2015. [PubMed: 26522471] [Full Text: https://doi.org/10.1016/j.ajhg.2015.09.011]


Contributors:
Bao Lige - updated : 08/01/2022
Marla J. F. O'Neill - updated : 07/05/2022
Patricia A. Hartz - updated : 02/15/2018
Ada Hamosh - updated : 1/19/2016
Marla J. F. O'Neill - updated : 2/24/2015
Ada Hamosh - updated : 2/8/2012
Marla J. F. O'Neill - updated : 8/3/2011
Ada Hamosh - updated : 10/6/2009
Matthew B. Gross - updated : 8/3/2009
Patricia A. Hartz - updated : 8/3/2009
Paul J. Converse - updated : 3/13/2008
Anne M. Stumpf - updated : 1/16/2008
Victor A. McKusick - updated : 12/28/2007
Paul J. Converse - updated : 1/10/2006
Stylianos E. Antonarakis - updated : 9/24/2002
Anne M. Lopez - updated : 12/22/1998

Creation Date:
Victor A. McKusick : 5/15/1991

Edit History:
alopez : 08/29/2022
alopez : 08/01/2022
alopez : 07/05/2022
alopez : 08/06/2021
alopez : 05/15/2019
mgross : 02/15/2018
carol : 08/31/2016
carol : 05/27/2016
alopez : 1/19/2016
alopez : 12/29/2015
carol : 5/7/2015
carol : 2/26/2015
carol : 2/26/2015
mcolton : 2/24/2015
alopez : 2/10/2012
terry : 2/8/2012
carol : 9/20/2011
wwang : 8/5/2011
terry : 8/3/2011
alopez : 10/15/2009
terry : 10/6/2009
mgross : 8/3/2009
terry : 8/3/2009
mgross : 3/17/2008
mgross : 3/14/2008
terry : 3/13/2008
alopez : 1/17/2008
alopez : 1/16/2008
terry : 12/28/2007
mgross : 1/10/2006
mgross : 9/24/2002
joanna : 6/19/2000
alopez : 6/19/2000
terry : 1/15/1999
carol : 12/22/1998
alopez : 12/22/1998
alopez : 9/4/1998
carol : 2/1/1993
carol : 1/29/1993
carol : 1/5/1993
carol : 12/14/1992
supermim : 3/16/1992
carol : 3/2/1992