* 601906

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 10B; WNT10B


HGNC Approved Gene Symbol: WNT10B

Cytogenetic location: 12q13.12     Genomic coordinates (GRCh38): 12:48,965,340-48,971,735 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12q13.12 Split-hand/foot malformation 6 225300 AR 3
Tooth agenesis, selective, 8 617073 AD 3

TEXT

Cloning and Expression

Several members of the Wnt gene family have been shown to cause mammary tumors in mice. Using degenerate primer PCR on human genomic DNA and specific PCR of cDNA libraries, Bui et al. (1997) isolated a Wnt gene that had not previously been described in human. It is the human homolog of mouse Wnt10b, which had been shown to be one of the oncogenes cooperating with FGF3 (164950) in the development of mouse mammary tumor virus (MMTV)-induced mammary carcinomas in mice. The human WNT10B sequence is 88% and 95% identical to the mouse gene at nucleotide and amino acid levels, respectively. WNT10B expression was not observed in normal and benign proliferations of human breast tissue but was found to be elevated in 3 of 50 primary breast carcinomas. Southern blot analysis of the carcinoma expressing the highest level of WNT10B showed no amplification or rearrangement of the gene.

Hardiman et al. (1997) demonstrated that the WNT10B gene encodes a 389-amino acid protein with 96.6% sequence identity to mouse Wnt10b. The expression pattern showed that it is synthesized in many adult tissues with the highest levels found in heart and skeletal muscle.

Yu et al. (2016) examined the temporal and spatial expression pattern of Wnt10b in whole-mount mouse embryos from embryonic day (E) 11.5 to E15.5, and found that compared to other embryonic tissues, the developing tooth field showed specific expression of Wnt10b, which was particularly high in the incisors at the E14.5 cap stage. Expression of the Wnt10b receptor Lrp6 (603507) overlapped that of Wnt10b, and expression of 2 additional crucial components, Axin2 (604025) and Dvl1 (601365), was also detectable at the cap stage.


Gene Structure

By analyzing human genome draft sequence, Kirikoshi et al. (2001) determined that WNT10B is encoded by 5 exons and is clustered with WNT1 (164820) in a head-to-head manner with an interval of less than 7 kb. They hypothesized that the WNT1-WNT10B gene cluster and the WNT6 (604663)-WNT10A (606268) gene cluster on chromosome 2 might be due to duplication of an ancestral WNT gene cluster.


Mapping

By YAC and fluorescence in situ hybridization (FISH) mapping, Bui et al. (1997) localized the WNT10B gene to 12q13, a chromosomal region frequently rearranged in human tumors and also containing the WNT1 gene (164820).

By PCR typing of a human/rodent monochromosomal panel and FISH, Hardiman et al. (1997) mapped the WNT10B gene to chromosome 12q13.1.


Gene Function

Ross et al. (2000) showed that WNT signaling, likely mediated by WNT10B, is a molecular switch that governs adipogenesis. WNT signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors CEBPA (116897) and PPAR-gamma (601487). When WNT signaling in preadipocytes is prevented by overexpression of axin (603816) or dominant-negative TCF4 (TCF7L2; 602228), these cells differentiate into adipocytes. Disruption of WNT signaling also causes transdifferentiation of myoblasts into adipocytes in vitro, highlighting the importance of this pathway not only in adipocyte differentiation but also in mesodermal cell fate determination.

Li et al. (2020) found that parathyroid hormone (PTH) treatment did not induce bone anabolism in germ-free mice and antibiotic-treated conventional mice, in contrast with controls. Further analysis revealed that butyrate, a metabolite produced by gut microbiota that facilitates gut-bone communication, was required for PTH to stimulate bone formation and increase bone mass. Butyrate enabled PTH to expand the number of bone marrow regulatory T cells (Tregs) via Gpr43 (603823) signaling in dendritic cells and Gpr43-independent targeting of Cd4 (186940)-independent T cells. Tregs stimulated release of Wnt10b by bone marrow Cd8 (see 186910)-positive T cells, which activated Wnt-dependent bone formation.


Molecular Genetics

Split-Hand/Foot Malformation 6

In a consanguineous Turkish family with SHFM mapping to chromosome 12q31.11-q13 (SHFM6; 225300), originally reported by Gul and Oktenli (2002), Ugur and Tolun (2008) analyzed the candidate gene WNT10B and identified homozygosity for a missense mutation (R332W; 601906.0001) in all but the most mildly affected individual; it was also found in homozygosity in 1 unaffected family member. Ugur and Tolun (2008) proposed that either a second locus contributed to the phenotype or a suppressor locus prevented trait manifestation in the nonpenetrant female. Linkage analysis for the 5 known SHFM loci (see SHFM1, 183600) excluded 4 of them; however, a rare insertion polymorphism (rs34201045) at an alternate promoter used for transcription of an N-terminal-truncated p63 isotype (see TP63, 603273) was detected in heterozygosity or homozygosity in all but 1 affected individual.

In a 30-year-old pregnant Swiss woman with SHFM6, who presented for genetic counseling, Blattner et al. (2010) identified a homozygous truncating mutation in the WNT10B gene (601906.0001). Blattner et al. (2010) emphasized that this patient, who presented with apparent sporadic occurrence of the disorder and could have been presumed to have a de novo dominant mutation, was found to be homozygous for the WNT10B mutation, resulting in serious implications for genetic counseling.

In a 9-month-old girl, born to consanguineous Indian parents, with SHSFM6, Kantaputra et al. (2018) identified a homozygous mutation in the WNT10B gene (601906.0005). The girl also had sparse hair and interrupted eyebrows. Both parents and her sister were unaffected and were heterozygous for the mutation.

Selective Tooth Agenesis 8

In 3 affected members of a Chinese family and 3 sporadic patients with selective tooth agenesis (STHAG8; 617073), Yu et al. (2016) identified heterozygosity for 1 nonsense and 3 missense mutations in the WNT10B gene (see, e.g., 601906.0003 and 601906.0004). Functional analysis demonstrated that the mutants could not efficiently induce endothelial differentiation of dental pulp stem cells.


Animal Model

Stevens et al. (2010) generated Wnt10b-null mice and observed statistically significant increases in bone volume fraction and trabecular number, with concurrent decreases in trabecular spacing, compared to wildtype mice at 1 month of age. However, beginning at 2 months of age, the mutant mice showed progressive reductions in trabecular mass, with significantly reduced bone volume fraction and trabecular number as well as increased trabecular spacing, but no difference in trabecular and cortical thickness. Wnt10b heterozygotes also displayed a loss of trabecular bone at 6 months of age. Histomorphometric analysis in Wnt10b-null mice showed no difference in osteoblast or osteoclast number per trabecular bone area, nor an increase in osteoclast activity, indicating that the age-progressive osteopenia was due to decreased bone deposition rather than increased bone resorption. Analysis of primary bone marrow stromal cells revealed a 50% decrease in the number of osteogenic as well as adipogenic centers at 6 months of age. Quantification of mesenchymal stem cells in Mesencult medium showed a 40% reduction in Wnt10b-null multipotential mesenchymal progenitors by 6 months. Stevens et al. (2010) concluded that their results extended the role for Wnt signaling in development and postnatal bone homeostasis, providing evidence that WNT10B is an endogenous Wnt ligand operating in bone and that it functions to maintain mesenchymal and/or osteoblast progenitors in adult bone.


ALLELIC VARIANTS ( 5 Selected Examples):

.0001 SPLIT-HAND/FOOT MALFORMATION 6

WNT10B, ARG332TRP
  
RCV000008069...

In affected members of a consanguineous Turkish family with split-hand/foot malformation-6 (SHFM6; 225300), originally reported by Gul and Oktenli (2002), Ugur and Tolun (2008) identified homozygosity for a 994C-T transition in exon 5 of the WNT10B gene, resulting in an arg332-to-trp (R332W) substitution at a highly conserved residue. The mutation, which was not detected in 200 controls, was not found in the most mildly affected individual, a man with only cutaneous syndactyly of the right hand; however, it was present in homozygosity in 1 unaffected female family member. All but 1 affected individual also carried a TP63 (603273) promoter polymorphism, rs34201045, in homozygosity or heterozygosity.


.0002 SPLIT-HAND/FOOT MALFORMATION 6

WNT10B, 4-BP DUP, 458AGCA
  
RCV000023161

In a 30-year-old pregnant Swiss woman with split-hand/foot malformation-6 (SHFM6; 225300) who presented for genetic counseling, Blattner et al. (2010) identified a homozygous 4-bp duplication (458dupAGCA) in exon 4 of the WNT10B gene, resulting in a frameshift and premature termination. Both unaffected parents and several other unaffected family members were heterozygous for the mutation. Consanguinity of the parents of the patient was not known. At 12 years of age, based on radiographs, the malformation was described as presenting with loss of second, third, and fourth toes of both feet, bifid fifth toe on the right foot and fusion of the third and fourth metatarsal of both feet. A surgical osteotomy of the fourth and fifth metatarsal on the right foot was performed at 5 years. The right hand impressed at birth with complete cutaneous syndactyly of the fourth and fifth finger, hypoplasia of the third finger with loss of the distal phalanx. The left hand showed proximal cutaneous syndactyly of the third and fourth finger. Blattner et al. (2010) emphasized that this patient, who presented with apparent sporadic occurrence of the disorder and could have been presumed to have a de novo dominant mutation, was found to be homozygous for the WNT10B mutation, resulting in serious implications for genetic counseling.


.0003 TOOTH AGENESIS, SELECTIVE, 8

WNT10B, ARG211GLN
  
RCV000239578

In a mother, daughter, and son from a Chinese family (family ZZYWL-2) with selective tooth agenesis (STHAG8; 617073), Yu et al. (2016) identified heterozygosity for a c.632G-A transition (c.632G-A, NM_003394.3) in the WNT10B gene, resulting in an arg211-to-gln (R211Q) substitution at a highly conserved residue within the WNT domain. The mutation was not present in unaffected members of the family, but 1 allele of the variant was found in an in-house Han Chinese exome database of 2,200 individuals, and 1 was also found among 60,669 individuals in the ExAC database. Functional analysis in transfected HEPG2 epithelial cells demonstrated significantly lower luciferase activity with the R211Q mutant than with wildtype WNT10B. In addition, dental pulp stem cells showed impaired endothelial differentiation when treated with conditioned media containing the mutant compared to wildtype.


.0004 TOOTH AGENESIS, SELECTIVE, 8

WNT10B, TRP262TER
  
RCV000239472

In a 20-year-old Chinese woman (H3-63) with selective tooth agenesis (STHAG8; 617073), Yu et al. (2016) identified heterozygosity for a c.786G-A transition (c.786G-A, NM_003394.3) in the WNT10B gene, resulting in a trp262-to-ter (W262X) substitution at a conserved residue within the WNT domain. The mutation was not detected in an in-house Han Chinese exome database of 2,200 individuals, but 1 variant allele was found among 60,669 individuals in the ExAC database. Functional analysis in transfected HEPG2 epithelial cells demonstrated total absence of luciferase activity with the W262X mutant compared to wildtype WNT10B. In addition, dental pulp stem cells showed impaired endothelial differentiation when treated with conditioned media containing the mutant compared to wildtype.


.0005 SPLIT-HAND/FOOT MALFORMATION 6

WNT10B, 3-BP DEL, 695ACA (rs776938956)
  
RCV000735854

By direct sequencing of the WNT10B gene in a 9-month-old girl, born of consanguineous Indian parents, with split-hand/foot malformation (SHFM6; 225300), Kantaputra et al. (2018) identified homozygosity for a 3-bp deletion (c.695_697delACA, NM_003394.3), resulting in the in-frame deletion of a highly conserved asparagine residue at position 232 (Asn232del). The unaffected parents and sib of the patient were heterozygous for the mutation. The variant was found at a low frequency (0.000008) in the ExAC database and was not found in 100 normal controls. Structural modeling showed that asn232 lies in the middle a long alpha-helix in the palm domain, suggesting that its deletion would likely affect protein structure and function.


REFERENCES

  1. Blattner, A., Huber, A. R., Rothlisberger, B. Homozygous nonsense mutation in WNT10B and sporadic split-hand/foot malformation (SHFM) with autosomal recessive inheritance. Am. J. Med. Genet. 152A: 2053-2056, 2010. [PubMed: 20635353, related citations] [Full Text]

  2. Bui, T. D., Rankin, J., Smith, K., Huguet, E. L., Ruben, S., Strachan, T., Harris, A. L., Lindsay, S. A novel human Wnt gene, WNT10B, maps to 12q13 and is expressed in human breast carcinomas. Oncogene 14: 1249-1253, 1997. [PubMed: 9121776, related citations] [Full Text]

  3. Gul, D., Oktenli, C. Evidence for autosomal recessive inheritance of split hand/split foot malformation: a report of nine cases. Clin. Dysmorph. 11: 183-186, 2002. [PubMed: 12072797, related citations] [Full Text]

  4. Hardiman, G., Kastelein, R. A., Bazan, J. F. Isolation, characterization and chromosomal localization of human WNT10B. Cytogenet. Cell Genet. 77: 278-282, 1997. [PubMed: 9284937, related citations] [Full Text]

  5. Kantaputra, P. N., Kapoor, S., Verma, P., Intachai, W., Ketudat Cairns, J. R. Split hand-foot malformation and a novel WNT10B mutation. Europ. J. Med. Genet. 61: 372-375, 2018. [PubMed: 29427788, related citations] [Full Text]

  6. Kirikoshi, H., Sekihara, H., Katoh, M. WNT10A and WNT6, clustered in human chromosome 2q35 region with head-to-tail manner, are strongly coexpressed in SW480 cells. Biochem. Biophys. Res. Commun. 283: 798-805, 2001. [PubMed: 11350055, related citations] [Full Text]

  7. Li, J.-Y., Yu, M., Pal, S., Tyagi, A. M., Dar, H., Adams, J., Weitzmann, M. N., Jones, R. M., Pacifici, R. Parathyroid hormone-dependent bone formation requires butyrate production by intestinal microbiota. J. Clin. Invest. 130: 1767-1781, 2020. [PubMed: 31917685, related citations] [Full Text]

  8. Ross, S. E., Hemati, N., Longo, K. A., Bennett, C. N., Lucas, P. C., Erickson, R. L., MacDougald, O. A. Inhibition of adipogenesis by Wnt signaling. Science 289: 950-953, 2000. [PubMed: 10937998, related citations] [Full Text]

  9. Stevens, J. R., Miranda-Carboni, G. A., Singer, M. A., Brugger, S. M., Lyons, K. M., Lane, T. F. Wnt10b deficiency results in age-dependent loss of bone mass and progressive reduction of mesenchymal progenitor cells. J. Bone Miner. Res. 25: 2138-2147, 2010. [PubMed: 20499361, images, related citations] [Full Text]

  10. Ugur, S. A., Tolun, A. Homozygous WNT10b mutation and complex inheritance in split-hand/foot malformation. Hum. Molec. Genet. 17: 2644-2653, 2008. [PubMed: 18515319, related citations] [Full Text]

  11. Yu, P., Yang, W., Han, D., Wang, X., Guo, S., Li, J., Li, F., Zhang, X., Wong, S.-W., Bai, B., Liu, Y., Du, J., Sun, Z. S., Shi, S., Feng, H., Cai, T. Mutations in WNT10B are identified in individuals with oligodontia. Am. J. Hum. Genet. 99: 195-201, 2016. [PubMed: 27321946, images, related citations] [Full Text]


Bao Lige - updated : 10/27/2020
Sonja A. Rasmussen - updated : 10/07/2019
Marla J. F. O'Neill - updated : 08/15/2016
Cassandra L. Kniffin - updated : 1/11/2011
Marla J. F. O'Neill - updated : 8/17/2009
Dawn Watkins-Chow - updated : 10/8/2001
Ada Hamosh - updated : 8/10/2000
Victor A. McKusick - updated : 10/20/1997
Creation Date:
Victor A. McKusick : 6/27/1997
mgross : 10/27/2020
carol : 10/07/2019
carol : 12/22/2017
carol : 08/16/2016
carol : 08/15/2016
wwang : 01/28/2011
ckniffin : 1/11/2011
carol : 8/17/2009
mgross : 11/14/2007
joanna : 10/29/2001
carol : 10/8/2001
alopez : 8/10/2000
terry : 8/10/2000
carol : 7/28/1998
dkim : 7/17/1998
jenny : 10/22/1997
terry : 10/20/1997
mark : 7/1/1997
mark : 6/27/1997

* 601906

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 10B; WNT10B


HGNC Approved Gene Symbol: WNT10B

Cytogenetic location: 12q13.12     Genomic coordinates (GRCh38): 12:48,965,340-48,971,735 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12q13.12 Split-hand/foot malformation 6 225300 Autosomal recessive 3
Tooth agenesis, selective, 8 617073 Autosomal dominant 3

TEXT

Cloning and Expression

Several members of the Wnt gene family have been shown to cause mammary tumors in mice. Using degenerate primer PCR on human genomic DNA and specific PCR of cDNA libraries, Bui et al. (1997) isolated a Wnt gene that had not previously been described in human. It is the human homolog of mouse Wnt10b, which had been shown to be one of the oncogenes cooperating with FGF3 (164950) in the development of mouse mammary tumor virus (MMTV)-induced mammary carcinomas in mice. The human WNT10B sequence is 88% and 95% identical to the mouse gene at nucleotide and amino acid levels, respectively. WNT10B expression was not observed in normal and benign proliferations of human breast tissue but was found to be elevated in 3 of 50 primary breast carcinomas. Southern blot analysis of the carcinoma expressing the highest level of WNT10B showed no amplification or rearrangement of the gene.

Hardiman et al. (1997) demonstrated that the WNT10B gene encodes a 389-amino acid protein with 96.6% sequence identity to mouse Wnt10b. The expression pattern showed that it is synthesized in many adult tissues with the highest levels found in heart and skeletal muscle.

Yu et al. (2016) examined the temporal and spatial expression pattern of Wnt10b in whole-mount mouse embryos from embryonic day (E) 11.5 to E15.5, and found that compared to other embryonic tissues, the developing tooth field showed specific expression of Wnt10b, which was particularly high in the incisors at the E14.5 cap stage. Expression of the Wnt10b receptor Lrp6 (603507) overlapped that of Wnt10b, and expression of 2 additional crucial components, Axin2 (604025) and Dvl1 (601365), was also detectable at the cap stage.


Gene Structure

By analyzing human genome draft sequence, Kirikoshi et al. (2001) determined that WNT10B is encoded by 5 exons and is clustered with WNT1 (164820) in a head-to-head manner with an interval of less than 7 kb. They hypothesized that the WNT1-WNT10B gene cluster and the WNT6 (604663)-WNT10A (606268) gene cluster on chromosome 2 might be due to duplication of an ancestral WNT gene cluster.


Mapping

By YAC and fluorescence in situ hybridization (FISH) mapping, Bui et al. (1997) localized the WNT10B gene to 12q13, a chromosomal region frequently rearranged in human tumors and also containing the WNT1 gene (164820).

By PCR typing of a human/rodent monochromosomal panel and FISH, Hardiman et al. (1997) mapped the WNT10B gene to chromosome 12q13.1.


Gene Function

Ross et al. (2000) showed that WNT signaling, likely mediated by WNT10B, is a molecular switch that governs adipogenesis. WNT signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors CEBPA (116897) and PPAR-gamma (601487). When WNT signaling in preadipocytes is prevented by overexpression of axin (603816) or dominant-negative TCF4 (TCF7L2; 602228), these cells differentiate into adipocytes. Disruption of WNT signaling also causes transdifferentiation of myoblasts into adipocytes in vitro, highlighting the importance of this pathway not only in adipocyte differentiation but also in mesodermal cell fate determination.

Li et al. (2020) found that parathyroid hormone (PTH) treatment did not induce bone anabolism in germ-free mice and antibiotic-treated conventional mice, in contrast with controls. Further analysis revealed that butyrate, a metabolite produced by gut microbiota that facilitates gut-bone communication, was required for PTH to stimulate bone formation and increase bone mass. Butyrate enabled PTH to expand the number of bone marrow regulatory T cells (Tregs) via Gpr43 (603823) signaling in dendritic cells and Gpr43-independent targeting of Cd4 (186940)-independent T cells. Tregs stimulated release of Wnt10b by bone marrow Cd8 (see 186910)-positive T cells, which activated Wnt-dependent bone formation.


Molecular Genetics

Split-Hand/Foot Malformation 6

In a consanguineous Turkish family with SHFM mapping to chromosome 12q31.11-q13 (SHFM6; 225300), originally reported by Gul and Oktenli (2002), Ugur and Tolun (2008) analyzed the candidate gene WNT10B and identified homozygosity for a missense mutation (R332W; 601906.0001) in all but the most mildly affected individual; it was also found in homozygosity in 1 unaffected family member. Ugur and Tolun (2008) proposed that either a second locus contributed to the phenotype or a suppressor locus prevented trait manifestation in the nonpenetrant female. Linkage analysis for the 5 known SHFM loci (see SHFM1, 183600) excluded 4 of them; however, a rare insertion polymorphism (rs34201045) at an alternate promoter used for transcription of an N-terminal-truncated p63 isotype (see TP63, 603273) was detected in heterozygosity or homozygosity in all but 1 affected individual.

In a 30-year-old pregnant Swiss woman with SHFM6, who presented for genetic counseling, Blattner et al. (2010) identified a homozygous truncating mutation in the WNT10B gene (601906.0001). Blattner et al. (2010) emphasized that this patient, who presented with apparent sporadic occurrence of the disorder and could have been presumed to have a de novo dominant mutation, was found to be homozygous for the WNT10B mutation, resulting in serious implications for genetic counseling.

In a 9-month-old girl, born to consanguineous Indian parents, with SHSFM6, Kantaputra et al. (2018) identified a homozygous mutation in the WNT10B gene (601906.0005). The girl also had sparse hair and interrupted eyebrows. Both parents and her sister were unaffected and were heterozygous for the mutation.

Selective Tooth Agenesis 8

In 3 affected members of a Chinese family and 3 sporadic patients with selective tooth agenesis (STHAG8; 617073), Yu et al. (2016) identified heterozygosity for 1 nonsense and 3 missense mutations in the WNT10B gene (see, e.g., 601906.0003 and 601906.0004). Functional analysis demonstrated that the mutants could not efficiently induce endothelial differentiation of dental pulp stem cells.


Animal Model

Stevens et al. (2010) generated Wnt10b-null mice and observed statistically significant increases in bone volume fraction and trabecular number, with concurrent decreases in trabecular spacing, compared to wildtype mice at 1 month of age. However, beginning at 2 months of age, the mutant mice showed progressive reductions in trabecular mass, with significantly reduced bone volume fraction and trabecular number as well as increased trabecular spacing, but no difference in trabecular and cortical thickness. Wnt10b heterozygotes also displayed a loss of trabecular bone at 6 months of age. Histomorphometric analysis in Wnt10b-null mice showed no difference in osteoblast or osteoclast number per trabecular bone area, nor an increase in osteoclast activity, indicating that the age-progressive osteopenia was due to decreased bone deposition rather than increased bone resorption. Analysis of primary bone marrow stromal cells revealed a 50% decrease in the number of osteogenic as well as adipogenic centers at 6 months of age. Quantification of mesenchymal stem cells in Mesencult medium showed a 40% reduction in Wnt10b-null multipotential mesenchymal progenitors by 6 months. Stevens et al. (2010) concluded that their results extended the role for Wnt signaling in development and postnatal bone homeostasis, providing evidence that WNT10B is an endogenous Wnt ligand operating in bone and that it functions to maintain mesenchymal and/or osteoblast progenitors in adult bone.


ALLELIC VARIANTS 5 Selected Examples):

.0001   SPLIT-HAND/FOOT MALFORMATION 6

WNT10B, ARG332TRP
SNP: rs121918349, gnomAD: rs121918349, ClinVar: RCV000008069, RCV003555964

In affected members of a consanguineous Turkish family with split-hand/foot malformation-6 (SHFM6; 225300), originally reported by Gul and Oktenli (2002), Ugur and Tolun (2008) identified homozygosity for a 994C-T transition in exon 5 of the WNT10B gene, resulting in an arg332-to-trp (R332W) substitution at a highly conserved residue. The mutation, which was not detected in 200 controls, was not found in the most mildly affected individual, a man with only cutaneous syndactyly of the right hand; however, it was present in homozygosity in 1 unaffected female family member. All but 1 affected individual also carried a TP63 (603273) promoter polymorphism, rs34201045, in homozygosity or heterozygosity.


.0002   SPLIT-HAND/FOOT MALFORMATION 6

WNT10B, 4-BP DUP, 458AGCA
SNP: rs763548858, gnomAD: rs763548858, ClinVar: RCV000023161

In a 30-year-old pregnant Swiss woman with split-hand/foot malformation-6 (SHFM6; 225300) who presented for genetic counseling, Blattner et al. (2010) identified a homozygous 4-bp duplication (458dupAGCA) in exon 4 of the WNT10B gene, resulting in a frameshift and premature termination. Both unaffected parents and several other unaffected family members were heterozygous for the mutation. Consanguinity of the parents of the patient was not known. At 12 years of age, based on radiographs, the malformation was described as presenting with loss of second, third, and fourth toes of both feet, bifid fifth toe on the right foot and fusion of the third and fourth metatarsal of both feet. A surgical osteotomy of the fourth and fifth metatarsal on the right foot was performed at 5 years. The right hand impressed at birth with complete cutaneous syndactyly of the fourth and fifth finger, hypoplasia of the third finger with loss of the distal phalanx. The left hand showed proximal cutaneous syndactyly of the third and fourth finger. Blattner et al. (2010) emphasized that this patient, who presented with apparent sporadic occurrence of the disorder and could have been presumed to have a de novo dominant mutation, was found to be homozygous for the WNT10B mutation, resulting in serious implications for genetic counseling.


.0003   TOOTH AGENESIS, SELECTIVE, 8

WNT10B, ARG211GLN
SNP: rs779326570, gnomAD: rs779326570, ClinVar: RCV000239578

In a mother, daughter, and son from a Chinese family (family ZZYWL-2) with selective tooth agenesis (STHAG8; 617073), Yu et al. (2016) identified heterozygosity for a c.632G-A transition (c.632G-A, NM_003394.3) in the WNT10B gene, resulting in an arg211-to-gln (R211Q) substitution at a highly conserved residue within the WNT domain. The mutation was not present in unaffected members of the family, but 1 allele of the variant was found in an in-house Han Chinese exome database of 2,200 individuals, and 1 was also found among 60,669 individuals in the ExAC database. Functional analysis in transfected HEPG2 epithelial cells demonstrated significantly lower luciferase activity with the R211Q mutant than with wildtype WNT10B. In addition, dental pulp stem cells showed impaired endothelial differentiation when treated with conditioned media containing the mutant compared to wildtype.


.0004   TOOTH AGENESIS, SELECTIVE, 8

WNT10B, TRP262TER
SNP: rs766021478, ClinVar: RCV000239472

In a 20-year-old Chinese woman (H3-63) with selective tooth agenesis (STHAG8; 617073), Yu et al. (2016) identified heterozygosity for a c.786G-A transition (c.786G-A, NM_003394.3) in the WNT10B gene, resulting in a trp262-to-ter (W262X) substitution at a conserved residue within the WNT domain. The mutation was not detected in an in-house Han Chinese exome database of 2,200 individuals, but 1 variant allele was found among 60,669 individuals in the ExAC database. Functional analysis in transfected HEPG2 epithelial cells demonstrated total absence of luciferase activity with the W262X mutant compared to wildtype WNT10B. In addition, dental pulp stem cells showed impaired endothelial differentiation when treated with conditioned media containing the mutant compared to wildtype.


.0005   SPLIT-HAND/FOOT MALFORMATION 6

WNT10B, 3-BP DEL, 695ACA ({dbSNP rs776938956})
SNP: rs776938956, gnomAD: rs776938956, ClinVar: RCV000735854

By direct sequencing of the WNT10B gene in a 9-month-old girl, born of consanguineous Indian parents, with split-hand/foot malformation (SHFM6; 225300), Kantaputra et al. (2018) identified homozygosity for a 3-bp deletion (c.695_697delACA, NM_003394.3), resulting in the in-frame deletion of a highly conserved asparagine residue at position 232 (Asn232del). The unaffected parents and sib of the patient were heterozygous for the mutation. The variant was found at a low frequency (0.000008) in the ExAC database and was not found in 100 normal controls. Structural modeling showed that asn232 lies in the middle a long alpha-helix in the palm domain, suggesting that its deletion would likely affect protein structure and function.


REFERENCES

  1. Blattner, A., Huber, A. R., Rothlisberger, B. Homozygous nonsense mutation in WNT10B and sporadic split-hand/foot malformation (SHFM) with autosomal recessive inheritance. Am. J. Med. Genet. 152A: 2053-2056, 2010. [PubMed: 20635353] [Full Text: https://doi.org/10.1002/ajmg.a.33504]

  2. Bui, T. D., Rankin, J., Smith, K., Huguet, E. L., Ruben, S., Strachan, T., Harris, A. L., Lindsay, S. A novel human Wnt gene, WNT10B, maps to 12q13 and is expressed in human breast carcinomas. Oncogene 14: 1249-1253, 1997. [PubMed: 9121776] [Full Text: https://doi.org/10.1038/sj.onc.1200936]

  3. Gul, D., Oktenli, C. Evidence for autosomal recessive inheritance of split hand/split foot malformation: a report of nine cases. Clin. Dysmorph. 11: 183-186, 2002. [PubMed: 12072797] [Full Text: https://doi.org/10.1097/00019605-200207000-00006]

  4. Hardiman, G., Kastelein, R. A., Bazan, J. F. Isolation, characterization and chromosomal localization of human WNT10B. Cytogenet. Cell Genet. 77: 278-282, 1997. [PubMed: 9284937] [Full Text: https://doi.org/10.1159/000134597]

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Contributors:
Bao Lige - updated : 10/27/2020
Sonja A. Rasmussen - updated : 10/07/2019
Marla J. F. O'Neill - updated : 08/15/2016
Cassandra L. Kniffin - updated : 1/11/2011
Marla J. F. O'Neill - updated : 8/17/2009
Dawn Watkins-Chow - updated : 10/8/2001
Ada Hamosh - updated : 8/10/2000
Victor A. McKusick - updated : 10/20/1997

Creation Date:
Victor A. McKusick : 6/27/1997

Edit History:
mgross : 10/27/2020
carol : 10/07/2019
carol : 12/22/2017
carol : 08/16/2016
carol : 08/15/2016
wwang : 01/28/2011
ckniffin : 1/11/2011
carol : 8/17/2009
mgross : 11/14/2007
joanna : 10/29/2001
carol : 10/8/2001
alopez : 8/10/2000
terry : 8/10/2000
carol : 7/28/1998
dkim : 7/17/1998
jenny : 10/22/1997
terry : 10/20/1997
mark : 7/1/1997
mark : 6/27/1997