Alternative titles; symbols
HGNC Approved Gene Symbol: KRT86
SNOMEDCT: 69488000; ICD10CM: Q84.1;
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:52,274,645-52,309,163 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | Monilethrix | 158000 | Autosomal dominant | 3 |
In addition to the epithelial, or soft, alpha-keratins, the keratin multigene family comprises the smaller family of hard alpha-keratins that, in accordance with their most frequently investigated site of expression, are referred to as hair keratins. Independent of species, the hair keratin family consists of several members of each of 2 subfamilies; according to Winter et al. (1997), 7 type I human hair keratins (e.g., KRTHA1; 601077) and 4 type II hair keratins had been identified.
Rogers et al. (1997) reviewed human hair keratin nomenclature. Expression studies showed that hair keratin synthesis is not restricted to the hair follicle and the cortex but clearly begins earlier in matrix cells of the hair bulb. Whereas both matrix and cuticle trichocytes appear to express only 1 keratin pair each, keratin expression in the cortex involves at least 4 sequentially synthesized, structurally highly related keratin pairs. The keratins have highly homologous central alpha-helical rod domains flanked by variable-sized head and tail domains. The boundary peptides at the extremities of the rod domain (the helix initiation motif (HIM) of the 1A subdomain and the helix termination motif (HTM) of the 2B subdomain) are highly conserved and crucial for structure and function. Pathogenic mutations, which have been described in epithelial alpha-keratins in a number of hereditary disorders of skin, skin appendages, and oral mucosa, appear most disruptive when located in the HIMs or HTMs of keratins.
By screening a human scalp cDNA library with a mouse genomic sequence corresponding to the C terminus and 3-prime noncoding region of Hb6, Rogers et al. (1997) isolated a cDNA encoding KRT86 (KRTHB6, or HB6). The predicted protein has 483 amino acids. The amino acid sequences of HB1 (KRT81; 602153), HB3 (HRT83; 602765), HB5 ( KRT85; 602767), and HB6 are highly conserved, with the similarity extending beyond the alpha-helical region into the N-terminal and proximal C-terminal domains. HB6 is more closely related to HB1 and HB3 than to HB5. In situ hybridization studies demonstrated that type II keratin genes are sequentially activated in the hair follicle in the following order: HB5--(HB1, HB3)--HB6. The synthesis of HB6 mRNA begins slightly higher in the hair shaft than HB1 and HB3 mRNA syntheses and continues much farther up, ending in the keratogenous zone.
Bowden et al. (1998) cloned the complete genomic sequence of HB6. The HB6 gene has 9 exons and spans about 7.1 kb from the translational initiation ATG codon to the poly(A) site. Its upstream regulatory sequences contain a LEF1 (153245)-binding site, which is found in other hair keratin genes.
Rogers et al. (1995) demonstrated that human hair keratin genes colocalize with epithelial keratin genes on 17q12-q21 (type I genes) and 12q13 (type II genes), respectively.
By fluorescence in situ hybridization, Bowden et al. (1998) mapped the HB6 gene to the type II hair keratin cluster on 12q13. The HB6 gene is about 10 kb from the HB1 gene.
Monilethrix (MNLIX; 158000) is an autosomal dominant hair disorder characterized clinically by alopecia and follicular papules. Affected hairs have uniform elliptical nodes of normal thickness and intermittent constrictions, internodes at which the hair easily breaks. Usually only the scalp is involved, but in severe forms, the secondary sexual hair, eyebrows, eyelashes, and nails may also be affected. The disorder has been linked to the type II keratin gene cluster on 12q13 in several pedigrees. Winter et al. (1997) analyzed a matrix basic keratin and 3 cortical basic keratins in a 4-generation British monilethrix family with known linkage to 12q13. The gene regions encoding HIM and HTM were amplified and sequenced. The authors detected a heterozygous G-to-A point mutation in the first position of the glutamic acid 413 codon GAG in the exon encoding the HTM of the cortical keratin HB6 in affected members of the family. The mutation led to a nonconservative glu413-to-lys (E413K; 601928.0001) substitution. A 3-generation French monilethrix family in which linkage analysis had not been performed also revealed a heterozygous point mutation in codon 413 in affected individuals, but in this case, a G-to-T transversion occurred at the third base of the codon and yielded a conservative substitution of aspartic acid for glutamic acid-413 (E413D; 601928.0002). Winter et al. (1997) predicted that, by analogy with epithelial keratins, a monilethrix phenotype should also be expected from mutations in the type I partner of HB6.
Winter et al. (1999) stated that causative mutations for monilethrix had been found only in 2 type II cortex keratins, HB6 and HB1. In these hair keratins, the HTM was the only site in which the mutations were located. They described the first mutation in the HIM in the H6 gene, a change from asn114 to asp (601928.0003). Winter et al. (1999) suggested that monilethrix is a disease of hair cortex and that causative mutations are restricted to type II hair keratins.
Winter et al. (1997) identified a glu413-to-lys (E413K) mutation in affected members in the hair cortical basic keratin 6 in a British monilethrix (MNLIX; 158000) family that had been previously been found to show linkage to a type II keratin cluster on 12q13. The mutation in the analogous glutamic acid residue of the type II epidermal keratin 2e has been identified in cases of ichthyosis bullosa of Siemens (600194.0002).
This mutation was originally designated GLU410LYS because the mutation was identified in a partial HB6 cDNA clone; based on the complete HB6 sequence reported by Bowden et al. (1998), Winter et al. (1998) revised the designation of the mutation to glu413 to lys. Glu413 to lys, the most frequently observed mutation in monilethrix, was also found by Korge et al. (1997) in 3 unrelated families.
Korge et al. (1998) sequenced the critical helix termination motif in the 2B domain of the KRTHB6 gene in 13 unrelated families or cases with monilethrix. In 5 of the 13 cases, they found the glu413-to-lys mutation. In 8 cases, however, including 3 in which linkage data were consistent with a defect in the type II keratin locus, no mutation was found in this domain. These findings demonstrate that codon 413 and the glutamic acid, which is residue 117 of the 2B helix, is a mutation hotspot for monilethrix.
Winter et al. (1999) stated that this mutation had been found in 22 cases of monilethrix.
In 15 affected members of 2 unrelated Indian families with monilethrix, Khandpur et al. (2004) identified the E413K mutation in the helix termination motif (HTM) in exon 7 of the KRTHB6 gene; in each family, the mutation segregated with polymorphisms in the HTM motif of the KRTHB1 gene (602153): 1 with 3 novel SNPs in cis and a second with only an intronic SNP. The 9 affected members of family 1 had a localized severe hair defect with beaded appearance confined to the scalp and carried the KRTHB1 polymorphisms in heterozygous state. The 6 affected members of family 2 had a generalized unbeaded hair defect of moderate severity and carried the KRTHB1 polymorphism with 3 SNPs in homozygous state. Presence of both the E413K mutation and variation in the KRTHB1 gene was not observed in 150 randomly selected unaffected controls.
In a French family with monilethrix (MNLIX; 158000), Winter et al. (1997) demonstrated a glu413-to-asp amino acid substitution (G413D) in the product of the HB6 gene. Although the same codon was involved as in the initially studied British patient (600194.0001), the disorder was clearly milder in the French family in which an adolescent's symptoms were restricted largely to keratosis pilaris of the limbs.
This mutation was originally designated GLU410ASP based on a partial HB6 cDNA clone; based on the complete HB6 sequence reported by Bowden et al. (1998), Winter et al. (1998) revised the designation of the mutation to glu413 to asp.
In a patient with monilethrix (MNLIX; 158000), Winter et al. (1999) identified a glu402-to-lys mutation (E402K) in the HTM of cortex keratin HB6 which was the equivalent of the E402K mutation of HB1 (602153.0002). The mutation was detected in only 1 clinically affected individual of an American family. Thus, the G-to-A transition represented a spontaneous germline mutation in the HB6 gene. This finding indicated that both the HB6/HB1 E413K substitution and the HB6/HB1 E402K substitution represent mutation hotspots in the HTM of the type II cortex keratins.
See also 601928.0005 and Pearce et al. (1999).
In an 18-year-old woman of Turkish descent with monilethrix, van Steensel et al. (2005) identified the E402K mutation.
In 11 affected members of a 3-generation consanguineous Turkish family segregating monilethrix, Celep et al. (2009) identified heterozygosity for the E402K mutation in the KRT86 gene. Noting the low (1.7) lod score obtained in this family at marker D12S390, the authors emphasized the difficulties of mapping a heterozygous disorder in a country with a high rate of consanguinity.
Winter et al. (1999) described the first monilethrix (MNLIX; 158000)-causing mutation in the HIM of the cortex keratin HB6. The critical asn114-to-asp substitution was found only in affected members of a large Swedish 3-generation kindred. Considering that since childhood, half of the affected individuals suffered from complete baldness and follicular keratosis, the HIM mutation seemed to be associated with a rather severe disease phenotype.
Pearce et al. (1999) studied 2 unrelated monilethrix (MNLIX; 158000) patients and identified heterozygosity for 2 different mutations in the same codon in exon 7 of the KRTHB6 gene. Both mutations affected the first base of codon 402 (glutamic acid). In one patient, a G-to-C transversion occurred causing a glutamine substitution (GAG to CAG; E402Q), whereas in the second patient, a G-to-A transition yielded a lysine residue (GAG to AAG; E402K 601928.0003). Both mutations disrupted a TaqI restriction site and RFLP analysis showed that a diagnostic 361-bp fragment could confirm the presence of the mutation.
In affected members of a 3-generation French family with monilethrix (MNLIX; 158000), Winter et al. (2000) identified a heterozygous C-to-A transversion in exon 1 of the KRT86 gene, resulting in an ala118-to-glu (A118E) substitution in the helix initiation motif. Winter et al. (2000) concluded that the mutation was incompatible with stable intermediate filament formation.
Bowden, P. E., Hainey, S. D., Parker, G., Jones, D. O., Zimonjic, D., Popescu, N., Hodgins, M. B. Characterization and chromosomal localization of human hair-specific keratin genes and comparative expression during the hair growth cycle. J. Invest. Derm. 110: 158-164, 1998. [PubMed: 9457912] [Full Text: https://doi.org/10.1046/j.1523-1747.1998.00097.x]
Celep, F., Uzumcu, A., Sonmez, F. M., Uyguner, O., Balci, Y. I., Bahadir, S., Karaguzel, A. Pitfalls of mapping a large Turkish consanguineous family with vertical monilethrix inheritance. Genet. Counsel. 20: 1-8, 2009. [PubMed: 19400537]
Khandpur, S., Bairwa, N. K., Reddy, B. S. N., Bamezai, R. A study of phenotypic correlation with the genotypic status of HTM regions of KRTHB6 and KRTHB1 genes in monilethrix families of Indian origin. Ann. Genet. 47: 77-84, 2004. [PubMed: 15050877] [Full Text: https://doi.org/10.1016/j.anngen.2003.07.003]
Korge, B. P., Healy, E., Munro, C. S., Punter, C., Birch-Machin, M., Holmes, S. C., Darlington, S., Hamm, H., Messenger, A. G., Rees, J. L., Traupe, H. A mutational hotspot in the 2B domain of human hair basic keratin 6 (hHb6) in monilethrix patients. J. Invest. Derm. 111: 896-899, 1998. [PubMed: 9804356] [Full Text: https://doi.org/10.1046/j.1523-1747.1998.00362.x]
Korge, B. P., Healy, E., Traupe, H., Punter, C., Mauch, C., Hamm, H., Birch-Machin, M. A., Belgaid, C. E., Stephenson, A. M., Holmes, S. C., Darlington, S., Messenger, A. G., Rees, J. L., Munro, C. S. Monilethrix is caused by mutation in the helix termination peptide of human type II hair keratin hHb6 in three families. (Abstract) J. Invest. Derm. 109: 409 only, 1997.
Pearce, E. G., Smith, S. K., Lanigan, S. W., Bowden, P. E. Two different mutations in the same codon of a type II hair keratin (hHb6) in patients with monilethrix. J. Invest. Derm. 113: 1123-1127, 1999. [PubMed: 10594761] [Full Text: https://doi.org/10.1046/j.1523-1747.1999.00777.x]
Rogers, M. A., Langbein, L., Praetzel, S., Moll, I., Krieg, T., Winter, H., Schweizer, J. Sequences and differential expression of three novel human type-II hair keratins. Differentiation 61: 187-194, 1997. [PubMed: 9084137] [Full Text: https://doi.org/10.1046/j.1432-0436.1997.6130187.x]
Rogers, M. A., Nischt, R., Korge, B., Krieg, T., Fink, T. M., Lichter, P., Winter, H., Schweizer, J. Sequence data and chromosomal localization of human type I and type II hair keratin genes. Exp. Cell Res. 220: 357-362, 1995. [PubMed: 7556444] [Full Text: https://doi.org/10.1006/excr.1995.1326]
van Steensel, M. A. M., Steijlen, P. M., Bladergroen, R. S., Vermeer, M., van Geel, M. A missense mutation in the type II hair keratin hHb3 is associated with monilethrix. J. Med. Genet. 42: e19, 2005. Note: Electronic Article. [PubMed: 15744029] [Full Text: https://doi.org/10.1136/jmg.2004.021030]
Winter, H., Clark, R. D., Tarras-Wahlberg, C., Rogers, M. A., Schweizer, J. Monilethrix: a novel mutation (glu402-to-lys) in the helix termination motif and the first causative mutation (asn114-to-asp) in the helix initiation motif of the type II hair keratin hHb6. J. Invest. Derm. 113: 263-266, 1999. [PubMed: 10469314] [Full Text: https://doi.org/10.1046/j.1523-1747.1999.00685.x]
Winter, H., Labreze, C., Chapalain, V., Surleve-Bazeille, J. E., Mercier, M., Rogers, M. A., Taieb, A., Schweizer, J. A variable monilethrix phenotype associated with a novel mutation, glu402lys, in the helix termination motif of the type II hair keratin hHb1. J. Invest. Derm. 111: 169-172, 1998. [PubMed: 9665406] [Full Text: https://doi.org/10.1046/j.1523-1747.1998.00234.x]
Winter, H., Rogers, M. A., Langbein, L., Stevens, H. P., Leigh, I. M., Labreze, C., Roul, S., Taieb, A., Krieg, T., Schweizer, J. Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix. Nature Genet. 16: 372-374, 1997. [PubMed: 9241275] [Full Text: https://doi.org/10.1038/ng0897-372]
Winter, H., Vabres, P., Larregue, M., Rogers, M. A., Schweizer, J. A novel missense mutation, A118E, in the helix initiation motif of the type II hair cortex keratin hHb6, causing monilethrix. Hum. Hered. 50: 322-324, 2000. [PubMed: 10878478] [Full Text: https://doi.org/10.1159/000022936]