Genomic Organization of the Human Hairless Gene (HR) and Identification of a Mutation Underlying Congenital Atrichia in an Arab Palestinian Family

Ahmad, Wasim; Zlotogorski, Abraham; Panteleyev, Andrey A.; Lam, HaMut; Siddique, M.; Haque, Muhammad Faiyaz ul; Abdallah, Husein M.; Dragan, Laryssa; Christiano, Angela M.

doi:10.1006/geno.1998.5699

Cited by 86 publications

(98 citation statements)

References 23 publications

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“…Because heterozygous mutants also display some HF abnormalities later in postnatal life, including spontaneous patches of alopecia after the third month of life (Panteleyev and Paus, unpublished observation), only those parameters of the first catagen transition of the ϩ/hr mice were used for comparison with hr/hr mice, which were histologically identical to normal catagen development in C57BL/6J mice. 18,23 All skin samples were harvested parallel to the dorsal midline to obtain longitudinal sections through the HF 24 and were processed for routine histology, immunohistochemistry, TUNEL stain, and histochemistry as described below. Skin samples of ϩ/hr mice of corresponding ages were used for comparison, after shaving their hair-bearing skin with a cordless trimmer.…”

Section: Animals and Tissue Collectionmentioning

confidence: 99%

The Role of the Hairless (hr) Gene in the. Regulation of Hair Follicle Catagen Transformation

Panteleyev¹,

Botchkareva²,

Sundberg³

et al. 1999

The American Journal of Pathology

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153

136

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Mice that carry a mutation at the hairless (hr) locus develop seemingly normal hair follicles (HF) but shed their hairs completely soon after birth. Histologically , their HFs degenerate into characteristic utriculi and dermal cysts shortly after the entry of the HF into the first regression phase (catagen) , during the initiation of HF cycling. Here , we show that at least nine distinct stages of HF disintegration can be distinguished in hr/hr mice. Toward the end of HF morphogenesis (day 15 postpartum) the proximal hair bulb in hr/hr skin undergoes premature and massive apoptosis. This is associated with a dyscoordination of cell proliferation in defined HF compartments, malpositioning of the proximal inner root sheath, striking atrophy of outer root sheath , and failure of trichilemmal keratinization in the developing club hair. Rather than undergoing their normal catagenassociated involution , the hair bulb and central outer root sheath disintegrate into separate cell clusters, thus disrupting all epithelial contact with the dermal papilla. Dermal papilla fibroblasts fail to migrate upward , and break up into clusters of shrunken cells stranded in the reticular dermis as dermal cyst precursors , while the upper HF epithelium transforms into utriculi. Some dermal papilla cells , which normally never undergo apoptosis , also become TUNEL؉ in hr/hr skin , and their normally high expression of a key adhesion molecule , neural cell adhesion molecule , declines. Thus , loss of a functional hr gene product (a putative zinc finger transcription factor) initiates a premature , highly dysregulated catagen, which results in the destruction of the normal HF architecture and abrogates the HF's ability to cycle. This provides new insights into the pathobiology of the hr mutation , and suggests that the normal hr gene product is a crucial element of catagen control. (Am J Pathol 1999, 155:159 -171)

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Section: Animals and Tissue Collectionmentioning

confidence: 99%

The Role of the Hairless (hr) Gene in the. Regulation of Hair Follicle Catagen Transformation

Panteleyev¹,

Botchkareva²,

Sundberg³

et al. 1999

The American Journal of Pathology

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153

136

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“…This form of hair loss is irreversible and histology is consistent with an absence of mature hair follicles. APL was mapped to chromosome 8p12 and mutations in the Hairless (HR) gene have been found in a growing number of APL patients [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. The diagnosis of APL requires detailed family history, especially of consanguinity, a clinical history, DNA sampling, and identification of a HR mutation.…”

Section: Introductionmentioning

confidence: 99%

“…The diagnosis of APL requires detailed family history, especially of consanguinity, a clinical history, DNA sampling, and identification of a HR mutation. Using these methods, we and others have identified several types of pathogenic HR mutations in multiple families of various ethnic backgrounds including nonsense, missense, insertion and deletion mutations [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Nonsense mutations in the hairless gene underlie APL in five families of Pakistani origin

Kim

Wajid

Kraemer

et al. 2007

Journal of Dermatological Science

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Abstract(1) Background-Atrichia with papular lesions (APL) is a rare autosomal recessive form of inherited alopecia. Affected individuals present with a distinct pattern of total hair loss on the scalp, axilla and body shortly after birth and are essentially devoid of eyelashes and eyebrows. This form of hair loss is irreversible and the histology is consistent with an absence of mature hair follicles. In addition to total atrichia, APL patients also present with papules and follicular cysts filled with cornified material. Mutations in the Hairless (HR) gene have been shown to underlie APL.(2) Objective-Here, we studied five unrelated large Pakistani families with clinical manifestations of APL.(3) Methods-Based on previous reports of HR mutations in APL, we performed direct DNA sequencing analysis.(4) Results-DNA sequencing of the HR gene in APL patients revealed three novel nonsense mutations in five unrelated families. All affected individuals were homozygous for a nonsense mutation due to C-to-T transitions at different positions in the amino acid sequence. Two families carry the mutation Q323X (CAG-TAG) in exon 3, two families harbor the mutation Q502X (CAG-TAG) in exon 6, and one family had a mutation at R940X (CGA-TGA) in exon 14. Haplotype analysis revealed that all affected individuals of both APL1 and APL16 families were homozygous for the same haplotype, and likewise, the mutation in families APL2 and APL19 was on the the same haplotype.(5) Conclusions-We report three novel nonsense mutations in the HR gene in APL. Two of the newly identified mutations, Q323X and Q502X, were found to be shared between unrelated families and marker analysis confirmed an identical homozygous haplotype for APL1 and APL16, and for APL2 and APL19. These findings suggest that Q323X and Q502X did not arise independently, but instead appear to have been propagated in the population. Collectively, these findings contribute further evidence for the involvement of hairless mutations in papular atrichia.

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“…The hairless (hr) gene is often responsible for this disorder. The gene is highly conserved between men, mice and rats [1,2,6]. The protein codified by this gene is a transcriptional corepressor for thyroid hormone receptors [13].…”

Section: Introductionmentioning

confidence: 99%

“…Experimental data suggest that the hr gene product may play a crucial role in maintaining the delicate balance between cell proliferation, differentiation and apoptosis in the hair follicle, as well as in the interfollicular epidermis [2].…”

Section: Introductionmentioning

confidence: 99%

The hairless (hr) gene is involved in the congenital hypotrichosis of Valle del Belice sheep

Finocchiaro¹,

Portolano²,

Damiani

et al. 2003

Genet. Sel. Evol.

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-Congenital hypotrichosis in mammalian species consists of partial or complete absence of hair at birth. The hairless gene is often responsible for this disorder in men, mice and rats. Recent experimental data on Valle del Belice sheep reared in Sicily for milk production, support the genetic control of the ovine hypotrichosis as a Mendelian recessive trait. The ovine hairless gene was chosen as the candidate gene involved in this disorder. Blood samples were collected from Valle del Belice sheep with the normal and hypotrichotic phenotypes. Almost the entire hairless gene was successfully amplified using the long PCR technique. Unrelated sheep with differing phenotypes were randomly chosen for sequencing the amplified products. Different mutations related to the hypotrichotic phenotype were found in exon 3. In fact, sequencing revealed an A/T transversion at position 739, a G/A transition at position 823, and a C/T transition at position 1312. From these nucleotide exchanges, three substitutions of the processed mature protein were deduced at the amino acid positions 247 (Thr/Ser), 275 (Ala/Thr), and 438 (Gln/Stop). A PCR-SSCP based test was developed in order to detect the last mutation, which is responsible for the hypotrichotic phenotype.hairless gene / congenital hypotrichosis / ovine / Valle del Belice sheep

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Genomic Organization of the Human Hairless Gene (HR) and Identification of a Mutation Underlying Congenital Atrichia in an Arab Palestinian Family

Cited by 86 publications

References 23 publications

The Role of the Hairless (hr) Gene in the. Regulation of Hair Follicle Catagen Transformation

The Role of the Hairless (hr) Gene in the. Regulation of Hair Follicle Catagen Transformation

Nonsense mutations in the hairless gene underlie APL in five families of Pakistani origin

The hairless (hr) gene is involved in the congenital hypotrichosis of Valle del Belice sheep

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