Alternative titles; symbols
HGNC Approved Gene Symbol: KRT31
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:41,393,721-41,397,608 (from NCBI)
Keratins are a group of proteins that belong to the intermediate filament family. Two classes of keratins are recognized: the epithelial keratins (e.g., KRT4, 123940), or soft alpha-keratins, which are expressed in the epidermis and the epithelia of many internal organs, and the hair keratins, or hard alpha-keratins, which are involved in the formation of hair and nails. Electrophoretic studies have divided the hair keratins into type I and type II subfamilies. Type I hair keratins, such as KRT31, are acidic and have molecular masses ranging from 40 to 48 kD, and type II hair keratins are basic to neutral and have molecular masses ranging from 58 to 65 kD. Heid et al. (1986) identified 8 major hair keratins, 4 of each type. Additional hair keratins have subsequently been discovered As with all intermediate filament subunit proteins, the hair keratins have a common secondary structure that consists of an N-terminal domain; 4 central alpha-helical coiled-coil domains, denoted 1A, 1B, 2A, and 2B; and a C-terminal domain. The non-alpha-helical domains of hair keratins have a high content of cysteine and proline residues, the former reflecting the use of disulfide bonding to produce a tougher, more durable structure. Sequence comparisons show that hair keratins within a subfamily have highly conserved alpha-helical and N-terminal domains but have C-terminal domains that are distinct in both sequence and length. Keratins are obligate heteropolymers, with distinct pairs of type I and type II proteins associating to form heterodimers; these further polymerize to produce the final 10-nm intermediate filament. Hair keratin genes are differentially expressed in the cuticle and cortex of the hair follicle (Heid et al., 1986; Yu et al., 1993; Rogers et al., 1997).
Heid et al. (1986), Rogers et al. (1997), and Schweizer et al. (2006) commented on the nomenclature of keratin genes.
Bowden et al. (1994) isolated a human HA1 genomic clone that contains sequences corresponding to the alpha-helical 2B domain, C-terminal region, and 3-prime untranslated region.
By screening a human scalp cDNA library with a mouse Ha1 sequence, Fink et al. (1995) isolated a cDNA encoding KRTHA1, or HA1. The predicted protein has 416 amino acids, including a 49-amino acid C-terminal domain, and a calculated molecular mass of 47.3 kD. The amino acid sequences of the human and mouse HA1 proteins are 89% identical. Northern blot analysis detected an approximately 1.7-kb HA1 transcript in human scalp but not hairless skin.
By in situ hybridization, Bowden et al. (1998) showed that HA1 was expressed in the differentiating cortex of growing (anagen) hair, with expression beginning 2 to 3 cell layers above the apex of the dermal papilla; expression was absent in the inner root sheath and medulla. No HA1 expression was detected during the resting stage (telogen) of the hair cycle.
Rogers et al. (1998) reported that the deduced KRTHA1 protein has 417 amino acids.
Langbein et al. (1999) reported the expression pattern of 9 type I hair keratin genes in the hair follicle. Hair keratin genes are also expressed in the tongue and thymus.
Approximately 5% of the human population express an acidic 41-kD protein that appears in the electrophoretic pattern of their hair keratins. This protein is inherited as an autosomal dominant trait and does not confer a distinct hair phenotype. Winter et al. (1997) found that the 41-kD protein is a truncated variant of HA1. They detected a G-to-A substitution in the 5-prime splice site of intron 6 of the HA1 gene that leads to the formation of an abnormally spliced HA1 mRNA species and the production of an HA1 protein lacking the entire nonhelical C-terminal domain. Winter et al. (1997) showed that the full-length and truncated HA1 proteins form identical keratin intermediate filaments when assembled in vitro with a type II hair keratin partner.
The gene structures within a keratin subfamily are generally conserved in the number and positions of introns, with type I genes containing 7 exons and type II genes containing 9 exons. Rogers et al. (1998) reported that the KRTHA1 gene contains 7 exons.
Type I hair keratin genes are clustered on chromosome 17q12-q21, and type II genes on chromosome 12q12-q13 (Rogers et al., 1995).
Rogers et al. (1998) isolated and characterized 2 overlapping human PAC clones that cover 190 kb on 17q12-q21 and contain 9 type I hair keratin genes, 1 transcribed hair keratin pseudogene (KRTHAP1), and 1 orphan exon. The order of the genes is 5-prime--KRTHA6 (604540)--KRTHA5 (602764)--KRTHA2 (602760)--orphan exon--KRTHA8 (604542)--KRTHA7 (604541)--pseudogene--KRTHA1--KRTHA4 (602763)--KRTHA3B (602762)--KRTHA3A (602761)--3-prime. The hair keratin genes range in size from 4.2 to 7.5 kb, and the genes are separated from each other by 5.5 to 18.4 kb; all are located within about 140 kb. Each gene is transcribed from the 5-prime to 3-prime direction. Based on sequence homologies, the genes can be grouped into 3 subclusters of tandemly arranged genes. One subcluster, group A, consists of KRTHA1, KRTHA3A, KRTHA3B, and KRTHA4, which share 89% overall amino acid identity. A second subcluster, group B, contains KRTHA7 and KRTHA8, as well as the hair keratin pseudogene, which the authors called HAA. The functional hair keratins and hypothetical HAA hair keratin share approximately 81% overall amino acid identity. The third subcluster, group C, consists of the structurally less related hair keratins KRTHA2, KRTHA5, and KRTHA6, which share about 70% amino acid identity.
The KRTHAP1 pseudogene is thought to have been inactivated by a single basepair substitution that introduced a premature TGA termination codon into exon 4. Large-scale genotyping of human, chimpanzee, and gorilla DNAs revealed the homozygous presence of this nonsense mutation in humans of different ethnic backgrounds, but its absence in the functional orthologous chimpanzee and gorilla genes. The relative numbers of synonymous and nonsynonymous substitutions in the human pseudogene and the homologous chimpanzee gene, as inferred by using the gorilla gene as an outgroup, suggest that the human gene was inactivated only recently, viz., less than 240,000 years ago. This implies that the hair keratin phenotype of hominids before that time, and after the Pan-Homo divergence some 5.5 million years ago, could have been identical to that of the great apes. In addition, the homozygous presence of the exon 4 nonsense mutation in the pseudogene in some of the earliest branching lineages among extant human populations lends strong support to the 'single African origin' hypothesis for the evolution of modern humans (Winter et al., 2001).
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]
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Fink, P., Rogers, M. A., Korge, B., Winter, H., Schweizer, J. A cDNA encoding the human type I hair keratin hHa1. Biochim. Biophys. Acta 1264: 12-14, 1995. [PubMed: 7578244] [Full Text: https://doi.org/10.1016/0167-4781(95)00122-w]
Heid, H. W., Werner, E., Franke, W. W. The complement of native alpha-keratin polypeptides of hair-forming cells: a subset of eight polypeptides that differ from epithelial cytokeratins. Differentiation 32: 101-119, 1986. [PubMed: 2431943] [Full Text: https://doi.org/10.1111/j.1432-0436.1986.tb00562.x]
Langbein, L., Rogers, M. A., Winter, H., Silke, P., Beckhaus, U., Rackwitz, H.-R., Schweizer, J. The catalog of human hair keratins. I. Expression of the nine type I members in the hair follicle. J. Biol. Chem. 274: 19874-19884, 1999. [PubMed: 10391933] [Full Text: https://doi.org/10.1074/jbc.274.28.19874]
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]
Rogers, M. A., Winter, H., Wolf, C., Heck, M., Schweizer, J. Characterization of a 190-kilobase pair domain of human type I hair keratin genes. J. Biol. Chem. 273: 26683-26691, 1998. [PubMed: 9756910] [Full Text: https://doi.org/10.1074/jbc.273.41.26683]
Schweizer, J., Bowden, P. E., Coulombe, P. A., Langbein, L., Lane, E. B., Magin, T. M., Maltais, L., Omary, M. B., Parry, D. A. D., Rogers, M. A., Wright, M. W. New consensus nomenclature for mammalian keratins. J. Cell Biol. 174: 169, 2006. [PubMed: 16831889] [Full Text: https://doi.org/10.1083/jcb.200603161]
Winter, H., Hofmann, I., Langbein, L., Rogers, M. A., Schweizer J. A splice site mutation in the gene of the human type I hair keratin hHa1 results in the expression of a tailless keratin isoform. J. Biol. Chem. 272: 32345-32352, 1997. [PubMed: 9405442] [Full Text: https://doi.org/10.1074/jbc.272.51.32345]
Winter, H., Langbein, L., Krawczak, M., Cooper, D. N., Jave-Suarez, L. F., Rogers, M. A., Praetzel, S., Heidt, P. J., Schweizer, J. Human type I hair keratin pseudogene phi-hHaA has functional orthologs in the chimpanzee and gorilla: evidence for recent inactivation of the human gene after the Pan-Homo divergence. Hum. Genet. 108: 37-42, 2001. [PubMed: 11214905] [Full Text: https://doi.org/10.1007/s004390000439]
Yu, J., Yu, D., Checkla, D. M., Freedberg, I. M., Bertolino, A. P. Human hair keratins. J. Invest. Derm. 101 (suppl. 1): 56S-59S, 1993. [PubMed: 7686952] [Full Text: https://doi.org/10.1111/1523-1747.ep12362635]