Hairless, Mouse, Homolog of

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OMIM Number

602302

Gene Map Locus
8p21.2

Description

Hair growth is a complex process. One of the key roles in this process is played by the thyroid hormone, which is essential for the regeneration of hair follicles. The hairless gene codes for a nuclear receptor co-repressor, which functions by turning off the expression of thyroid receptors. Interestingly, the hairless gene itself is triggered by thyroid hormone, thereby maintaining a balance of the effects of thyroid hormone on the brain and skin. Thus, mutations in the hairless gene actually result in partial or total hair loss.

At least two separate forms of hair loss are associated with mutations in the HR gene. Alopecia universalis congenita (ALUNC) is an autosomal recessive condition characterized by hair follicles devoid of hair. On the other hand, atrichia with papular lesions (APL), also an autosomal recessive disorder, is characterized by total hair loss accompanied with the presence of papular lesions all over the skin.

Molecular Genetics

The human hairless gene is located on chromosome 8p21.2, where it spans a total length of 17.4 Kb. The gene consists of 19 exons and codes for a protein weighing 127 KDa and comprising of 1189 amino acids. There are two different isoforms of this protein, differing from each other on the basis of the expression or lack of expression of exon 17. The isoform lacking exon 17 is specifically expressed in skin tissues, whereas the other, more abundant isoform is expressed in all tissues, but the skin.

Although the HR protein shows very little sequence identity to other nuclear receptor co-repressors, its mode of action is similar. The mechanism of repression is most likely through an associated histone deacetylase activity.

Epidemiology in the Arab World

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Other Reports

Oman

Cichon et al. (1998) characterized the cDNA sequence encoding the human hairless gene and linked it to autosomal recessive universal congenital alopecia in an Omani family with this condition. Comparison of murine hairless gene to human sequences databases identified Genbank EST AA025648 (isolated from infant brain) and R67180 (isolated from fetal heart); both having 80% sequence resemblance to the mouse hairless gene. The sequence of the cDNA was completed by 5' and 3' Rapid Amplification of cDNA Ends (RACE) and the amplification products were sub-cloned and sequenced. The composite human hairless cDNA obtained, contained an open reading frame of 3570 nucleotides (encoding 1189 amino acids), which showed 19 nucleotide substitutions (resulting in a 11 amino acid change) when compared to an already sequenced gene in the Genbank. The human gene showed 81% and 80% identity at the DNA and protein levels, respectively, to the mouse gene. The gene was chromosomally localized by using radiation hybrid mapping to chromosome 8p21.2. To identify the structure of the gene, primers corresponding to the distal ends of neighboring exons were used to amplify putative introns. The PCR products obtained were sequenced to determine the exon-intron boundaries. Gene expression studies using RNA blots detected weak signals in brain, testis and colon while trace expression was detected in liver, kidney, pancreas, spleen and thymus. Sequencing of cDNA clones revealed two different RNA species with the presence or absence of exon 17, which was further confirmed by a nested PCR technique. Upon studying the tissue distribution of the alternative transcripts, traces of hairless mRNA were present in all tissues studied except peripheral blood leukocytes. Skin was the only tissue with exclusive expression of the shorter transcript, while the kidneys and testis only expressed the longer transcript. The other tissues were found to express both transcripts, with the longer one having more intensity then the shorter form. Cichon et al. (1998) surmised that these tissue-specific differences in the proportions of transcripts would explain the tissue-specific disease phenotype in patients with isolated congenital alopecia. The sequence of the human hairless gene of one of the patients revealed a homozygous 5' splice site mutation downstream of exon 12 (nucleotide 2776+1, G-to-A). This mutation led to a reading frame shift in exon 13 with a premature stop codon in exon 14. The mutation was traced in the patient's family with SSCP analysis (as this mutation did not alter any known restriction enzyme cutting site), and it was found that healthy subjects were either heterozygous for the mutation or homozygous for the wild-type allele. This mutation was absent in 80 Omani controls.

Palestine

In five Palestinian families of Arab origin with atrichia with papular lesions, 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.

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 in a large consanguineous Palestinian family suffering from congenital atrichia. Together, the mutations led to a frameshift and premature termination. Obligate carriers in the family were heterozygous for the mutation.

Saudi Arabia

Betz et al. (2007) described a Saudi family affected with Alopecia Universalis Congenita. Sequencing of the HR gene identified a novel homozygous insertion mutation, c.2661dupG (p.Thr888DfsX38), in the HR gene in the proband and her affected brother. The mutation resulted in a frameshift in premature stop codon downstream. Both parents (half first cousins) and two unaffected siblings were heterozygous for this mutation, while another affected brother was also homozygous for the mutation.

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