Alternative titles; symbols
HGNC Approved Gene Symbol: HR
SNOMEDCT: 715963002;
Cytogenetic location: 8p21.3 Genomic coordinates (GRCh38): 8:22,114,419-22,131,052 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p21.3 | Alopecia universalis | 203655 | Autosomal recessive | 3 |
| Atrichia with papular lesions | 209500 | Autosomal recessive | 3 |
The HR gene encodes a nuclear receptor corepressor that is critical for the maintenance of hair growth (Potter et al., 2001).
Ahmad et al. (1998) delineated the entire coding sequence of the human 'hairless' gene, which consists of 1189 amino acids. The protein encoded by the human, mouse, and rat 'hairless' genes contains a single zinc finger domain with a novel and conserved 6-cysteine motif and is thought to function as a transcription factor, with structural homology to the GATA family (see 305371) and to Tsga (JMJD1A; 611512), a protein encoded by a gene expressed in rat testis. The expression pattern of the human HR gene was consistent with that observed in mouse and rat, with substantial expression in the brain and skin and trace expression elsewhere. Similar to previous studies in mouse and rat, human HR was substantially expressed in fibroblasts from hair-bearing skin and was most highly expressed in brain (Thompson, 1996).
Cichon et al. (1998) reported the cloning and characterization of the human homolog of the mouse 'hairless' gene. They showed that the human 'hairless' gene undergoes alternative splicing and that at least 2 isoforms generated by alternative usage of exon 17 are found in human tissues. The isoform containing exon 17 is the predominantly expressed isoform in all tissues but skin, where exclusive expression of the shorter isoform was observed. The authors speculated that this tissue-specific difference in the proportion of 'hairless' transcripts lacking exon 17 sequences could contribute to the tissue-disease phenotype observed in individuals with isolated congenital alopecia (203655).
Using RNA dot-blot analysis, Ahmad et al. (1999) detected highest levels of HR expression in human brain. They detected lower levels in colon, stomach, pituitary gland, salivary gland, small intestine, appendix, and fetal brain.
By genomic sequence analysis, Ahmad et al. (1999) determined that the HR gene contains 19 exons spanning more than 14 kb. Exon 1 contains the 5-prime UTR, exon 2 contains the initiating methionine, and exon 19 contains the 3-prime end of the coding sequence, the termination codon, and the 3-prime UTR.
The mouse Hr gene resides on chromosome 14, which shares homology of synteny with human 8p and 14q, among others. To determine the precise chromosomal localization of the human HR gene, Ahmad et al. (1998) used radiation hybrid mapping, which placed the human homolog on chromosome 8p12 in the region where they mapped the gene mutant in a Pakistani family with alopecia universalis.
By analysis of a radiation hybrid panel, Cichon et al. (1998) mapped the human HR gene to chromosome 8p21.2 between recombinant markers D8S261 and D8S1771, which are separated by an estimated physical distance of 6.8 Mb.
Hair growth occurs in unsynchronized cycles consisting of 3 phases: anagen (growth phase), catagen (shortening phase), and telogen (resting phase). Davies (1998) suggested that the 'hairless' gene product may regulate one of the transitional parts of this pathway. A long list of cytokines and growth factors, including members of the epidermal, fibroblast, and transforming growth factor families, has been implicated in the hair growth cycle, providing a variety of potential targets for transcriptional control by 'hairless.' Davies (1998) noted that sorting out the mechanism would naturally be of immense commercial, as well as academic, interest. They stated that 1 company had already advocated liposomes as an effective gene delivery vehicle for fatigued hair follicles and suggested that the phrase 'shampoo and set' could soon take on a whole new meaning.
Using yeast 2-hybrid and Far Western assays, Thompson and Bottcher (1997) showed that HR interacts directly and specifically with thyroid hormone receptor (TR; see 190120) in vitro. They concluded that HR can mediate transcriptional repression and suggested that its interaction with TR is part of an autoregulatory mechanism.
Potter et al. (2001) showed that HR functions as a transcriptional corepressor for TRs. Using Far Western, yeast 2-hybrid, and transfection assays, they identified 2 independent regions of HR that mediate interaction with the TR ligand-binding domain. Potter et al. (2001) demonstrated that HR can mediate TR-dependent transcriptional repression in the absence of ligand. Using coimmunoprecipitation assays and indirect immunofluorescence, they observed that HR interacts with histone deacetylases (HDACs; see 601241) in vivo and is localized to matrix-associated deacetylase (MAD) bodies. Potter et al. (2001) concluded that HR is a component of the corepressor machinery and may define a class of nuclear receptor corepressors that serve a more specialized role than ubiquitous corepressors.
Miller et al. (2001) reported a patient with vitamin D-resistant rickets type 2A (277440), a compound heterozygote for mutations in the VDR gene (601769.0013, 601769.0014), in which the phenotype of atrichia with papular lesions (APL; 209500) was identical to that seen in patients carrying mutations in the HR gene. Her skin showed an absence of normal hair follicles and the presence of follicular remnants and cysts. The cyst epithelium contained keratin-15 (148030)- and keratin-17 (148069)-positive cells, suggesting derivation from the hair follicle bulge and the presence of epithelial stem cells. These findings suggested that VDR and HR, which are both zinc finger proteins, may be in the same genetic pathway that controls postnatal cycling of the hair follicle.
Using luciferase reporter and GFP expression constructs, Wen et al. (2009) demonstrated that U2HR (HRURF; 619257) negatively regulates protein translation of HR mRNA. U2HR was identified as 1 of 4 upstream ORFs in the 5-prime UTR of the HR gene.
Alopecia Universalis Congenita
In affected members of a Pakistani family with congenital universal alopecia (ALUNC; 203655), Cichon et al. (1998) identified homozygosity for a missense mutation (V1136D; 602302.0002) in the HR gene. In affected members of a family with ALUNC from Oman, they identified a homozygous splice donor mutation (602302.0003).
In a 17-year-old girl of Arab Israeli origin with ALUNC, Klein et al. (2002) detected a homozygous missense mutation (D1012N; 602302.0012) in the HR gene. The mutation occurred at a conserved residue and was not present in 326 chromosomes from unrelated healthy Arab Israeli individuals.
Atrichia with Papular Lesions
In affected members of 5 Palestinian families of Arab origin with atrichia with papular lesions (APL; 209500), Zlotogorski et al. (1998) identified homozygosity for a 1-bp deletion mutation in the HR gene (602302.0005).
In a large consanguineous Israeli-Arab kindred with atrichia with papular lesions, Sprecher et al. (1999) identified a 1-bp deletion (3434delC; 602302.0006) in the HR gene. The deletion, located in exon 18, was predicted to cause a frameshift in the highly conserved C-terminal part of the HR protein, a region putatively involved in the transcription factor activity of the HR gene product.
In affected individuals from 5 unrelated consanguineous Pakistani families with generalized scalp and body alopecia, sparse eyebrows and lashes, and papules, Kim et al. (2007) identified homozygosity for 1 of 3 nonsense mutations in the HR gene. Microsatellite marker analysis showed that each of 2 sets of families carrying the same nonsense mutation had an identical homozygous haplotype, suggesting that the mutations did not arise independently but were propagated in the population. Kim et al. (2007) noted that, in keeping with previous reports, they did not observe any genotype/phenotype correlations.
Reclassified Variants
The T1022A variant (602302.0001) in the HR gene reported by Ahmad et al. (1998) has been reclassified as a variant of unknown significance. Ahmad et al. (1998) studied a large Pakistani kindred with ALUNC in 4 males and 7 females in a pattern consistent with autosomal recessive inheritance. By homozygosity mapping, linkage was established to a 6-cM interval on 8p12, where they authors also mapped the HR gene. Direct sequence analysis revealed a homozygous A-to-G transition (thr1022 to ala; 602302.0001) in exon 15 of the HR gene in all affected individuals and in heterozygous state in obligate carriers but not in unaffected family members. In addition to the total body hair loss that bears a striking resemblance to alopecia universalis, the hr/hr mouse exhibits a number of phenotypic effects not observed in the Pakistani family, including defective differentiation of thymocytes (Morrissey et al., 1980), as well as a unique sensitivity to ultraviolet radiation and chemically induced skin tumors (Gallagher et al., 1984).
Associations Pending Confirmation
To test the hypothesis that HR may be involved in androgenetic alopecia (AGA1; 109200), Hillmer et al. (2002) systematically screened HR for genetic variability by means of single-strand conformation analysis (SSCA) in 46 unrelated men with androgenetic alopecia. To test for an involvement of HR in the development of androgenetic alopecia, 7 common variants were genotyped in 61 families with 93 affected offspring. The results were analyzed with the transmission/disequilibrium test (TDT). SSCA showed 15 single-nucleotide substitutions: 8 missense mutations, 4 silent mutations, and 3 mutations in exon-flanking intronic sequences. TDT results showed a marginally significant association between androgenetic alopecia variants 3379-29G/T (P = 0.024) and 2611-68C/T (P = 0.047). These results, however, did not remain significant after applying the conservative Bonferroni correction for multiple testing. Hillmer et al. (2002) concluded that these results do not provide evidence for a strong involvement of HR in the development of androgenetic alopecia, although a minor role cannot be fully excluded.
Brooke (1926) described the 'hairless' (hr/hr) mouse. Stoye et al. (1988) demonstrated that the mutation arose from spontaneous integration of an endogenous murine leukemia provirus into intron 6 of the 'hairless' gene, resulting in aberrant splicing and only about 5% normal mRNA transcripts present in homozygous hr/hr mice (Cachon-Gonzalez et al., 1994).
Using a chemical mutagen, Nam et al. (2006) produced a recessive mutation in mice that resulted in wrinkled skin, long curved nails, and progressive irreversible hair loss within a month of birth. They identified a G-to-T transversion at nucleotide 3572 of Hr, leading to a gly960-to-trp (G960W) substitution in the vicinity of repression domain-3, as the causative mutation. The relative amounts of Hr mRNA and protein were slightly elevated in mutant mice. Quantitative real-time PCR analysis revealed increased expression of keratin complex-1 (KC1) and vitamin D receptor (VDR; 601769) and decreased expression of nuclear receptor subfamily-1 (NRS1) and keratin-associated protein 16-6 (KARTAP16-6) in mutant mice. Nam et al. (2006) concluded that the G960W substitution may alter the function of HR as a transcriptional corepressor.
This variant, formerly titled ALOPECIA UNIVERSALIS CONGENITA, has been reclassified based on the findings of Cichon et al. (1998).
In a large consanguineous Pakistani kindred with alopecia universalis congenita (ALUNC; 203655), Ahmad et al. (1998) demonstrated that 11 affected members had a homozygous mutation in the HR gene, converting codon 1022 from ACC (thr) to GCA (ala). Similar substitutions engineered into the Whn DNA-binding protein (600838) are known to abolish its transactivation potential (Schuddekopf et al., 1996), suggesting that the same may be true of 'hairless.'
In a note added in proof, Cichon et al. (1998) suggested that the thr1022-to-ala mutation found in the Pakistani kindred by Ahmad et al. (1998) is unlikely to account, in and of itself, for congenital universal alopecia. They studied the presence of this mutation in 606 German control individuals and found it in heterozygous state in 14 persons, resulting in an allele frequency of 1.2% (99% confidence interval, 0.5-2.2%). If thr1022-to-ala is a disease-causing mutation, one would expect a prevalence of congenital universal alopecia of at least 1 in 40,000, the latter corresponding to the expected number of homozygotes calculated from an allele frequency of 0.5%. Universal alopecia is, however, an exceedingly rare disorder. Despite an easily recognizable phenotype, only a small number of families have been reported from the entire world.
In a large inbred Pakistani family (ALPA1), previously reported by Ahmad et al. (1993) Cichon et al. (1998) found that individuals with congenital universal alopecia (ALUNC; 203655) had a homozygous missense mutation in the HR gene: a T-to-A transversion at nucleotide 3407, resulting in a val1136-to-asp (V1136D) substitution. The mutation segregated with the disorder and was not found in 384 Caucasian, 80 Omani, and 52 Pakistani control chromosomes.
In an Omani family (ALOM1), Cichon et al. (1998) found that individuals with congenital universal alopecia (ALUNC; 203655) were homozygous for a splice donor mutation in intron 12, a change from G to A at nucleotide 2776 at position +1. The mutation segregated with the disorder and was not found in 384 Caucasian, 80 Omani, and 52 Pakistani control chromosomes.
In 5 Palestinian families of Arab origin with atrichia with papular lesions (APL; 209500), Zlotogorski et al. (1998) reported a homozygous deletion mutation, 2147delC, in exon 9 of the HR gene that led to a frameshift and premature termination.
By RT-PCR, Sprecher et al. (1999) compared the coding sequence of the HR gene in fibroblast cell lines derived from an affected patient from a previously reported (Sprecher et al., 1998) large consanguineous Israeli-Arab kindred with atrichia with papular lesions (APL; 209500) and an unrelated individual. They identified a 1-bp deletion (3434delC) in the HR gene that cosegregated with the disease phenotype in the family.
Ahmad et al. (1999) studied a Japanese family with a single member affected with congenital atrichia (APL; 209500), whose clinical history was described in detail by Nomura and Hashimoto (1998). The proband was born with normal hair, which began to shed at the age of 6 months and progressed to complete hairlessness at the age of 1 year. Hair was absent from the scalp, axillae, pubis, and other parts of the body, and the eyebrows and eyelashes were sparse. She had the additional characteristic features of grouped cystic and papular lesions on the neck, buttocks, and thighs. A skin biopsy from the neck showed deep dermal keratinous cysts. The parents were consanguineous. She was found to have a C-to-T transition at nucleotide 1837 in exon 6 of the HR gene, resulting in the conversion of an arginine to a premature termination codon (R613X). The mutation was predicted to result in the absence of mRNA and functional protein, due to nonsense-mediated mRNA decay.
In affected individuals of a large inbred Arab Palestinian family with congenital atrichia (APL; 209500), Ahmad et al. (1999) identified a complex homozygous deletion in exon 3 of the HR gene consisting of a 1-bp deletion (C) at nucleotide 1256 and a 21-bp deletion at nucleotide 1261. The mutation, designated 256delC;1261del21, led to a frameshift and premature termination. Obligate carriers in the family were heterozygous for the mutation.
In a German family with 2 females with atrichia with papular lesions (APL; 209500), Henn et al. (2002) reported a complete deletion of the consensus AG of the acceptor splice site of intron 13 (2847-2delAG). This mutation was predicted to cause skipping of exon 14, resulting in frameshift and nonsense-mediated mRNA decay; retention of intron 13 in the mRNA; or activation of a cryptic splice site in intron 13. This deletion, found on the maternal allele, occurred in compound heterozygosity with a gln1176-to-ter (Q1176X) mutation in the paternal HR allele, predicted to result in a truncation of 14 amino acids from the wildtype protein.
For discussion of the gln1176-to-ter (Q1176X) substitution in the HR gene that was found in compound heterozygous state in 2 sisters with atrichia with papular lesions (APL; 209500) by Henn et al. (2002), see 602302.0010.
In a patient with alopecia universalis congenita (ALUNC; 203655), Klein et al. (2002) reported a homozygous asp1012-to-asn (D1012N) mutation resulting from a G-to-A transition at nucleotide 3034 of the HR gene. The mutation occurred at a position shown in the rat to affect hairless binding to thyroid hormone receptor (see 190120) (Potter et al., 2001).
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