title: Nonsense mutations in the hairless gene underlie APL in five families of Pakistani origin.
abstract: 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.
  
  
  OBJECTIVE
  Here, we studied five unrelated large Pakistani families with clinical manifestations of APL.
  
  
  METHODS
  Based on previous reports of HR mutations in APL, we performed direct DNA sequencing analysis.
  
  
  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 same haplotype.
  
  
  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.
authors.affiliation: Department of Dermatology, Columbia University, College of Physicians & Surgeons, 630 West 168th Street VC15 204A, New York, NY 10032, United States.
authors.forename: Hyunmi
authors.initials: H
authors.lastname: Kim
authors.forename: Muhammad
authors.initials: M
authors.lastname: Wajid
authors.forename: Liv
authors.initials: L
authors.lastname: Kraemer
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimomura
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
mesh_terms: D000505:Alopecia / Q000208:ethnology / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D010154:Pakistan; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C490267:HR protein, human; D014157:Transcription Factors