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Research Article| Volume 50, ISSUE 1, P25-30, April 2008

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Mutations in the hairless gene underlie APL in three families of Pakistani origin

      Summary

      Background

      Atrichia with papular lesions (APL) (OMIM#209500) is a rare autosomal recessively inherited form of irreversible alopecia characterized by papular lesions of keratin-filled cysts on various regions of the body. Males and females are equally affected and present with a distinct pattern of total hair loss on scalp, axilla and body. It begins shortly after birth with the development of hair loss, and patients are normally devoid of eyelashes and eyebrows. Mutations in the hairless (HR) gene have been previously shown to be responsible for APL.

      Objective

      In this study, we studied the molecular basis of APL in three unrelated families of Pakistani origin.

      Method

      Molecular analysis of the HR genes was performed on genomic DNA from probands and family members.

      Results

      DNA sequencing of the HR gene in family A revealed a novel homozygous 2 bp deletion in exon 6 leading to a frameshift and a downstream premature termination codon in exon 8 (1782-83delAG). In family B, we identified a novel homozygous deletion of a G nucleotide at the exon 15–intron 15 boundary, termed 3097delG. Family C carries a previously reported missense mutation consisting of an A-to-G transition at nucleotide 276 resulting in the mutation N970S in exon 14.

      Conclusion

      Two mutations identified in this study are novel mutations in the HR gene and extend the body of evidence implicating the hairless gene family in the pathogenesis of human skin disorders. The one previously reported mutation suggests it may represent a recurrent mutation, or alternatively, an allele that is widely dispersed around the world.

      Keywords

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      References

        • Irvine A.D.
        • Christiano A.M.
        Hair on a gene string: recent advances in understanding the molecular genetics of hair loss.
        Clin Exp Dermatol. 2001; 26: 59-71
        • Zlotogorski A.
        • Panteleyev A.A.
        • Aita V.M.
        • Christiano A.M.
        Clinical and molecular diagnostic criteria of congenital atrichia with papular lesions.
        J Invest Dermatol. 2001; 117: 1662-1665
        • Paradisi M.
        • Masse M.
        • Martinez-Mir A.
        • Lam H.
        • Pedicelli C.
        • Christiano A.M.
        Identification of a novel splice site mutation in the human hairless gene underlying atrichia with papular lesions.
        Eur J Dermatol. 2005; 15: 332-338
        • Damste J.
        • Prakken J.R.
        Atrichia with papular lesions: a variant of congenital ectodermal dysplasia.
        Dermatologica. 1954; 108: 114-117
        • Ahmad W.
        • Faiyaz ul Haque M.
        • Brancolini V.
        • Tsou H.C.
        • ul Haque S.
        • Lam H.
        • et al.
        Alopecia universalis associated with a mutation in the human hairless gene.
        Science. 1998; 279: 720-724
        • Nothen M.M.
        • Cichon S.
        • Vogt I.R.
        • Hemmer S.
        • Kruse R.
        • Knapp M.
        • et al.
        A gene for universal congenital alopecia maps to chromosome 8p21-22.
        Am J Hum Genet. 1998; 62: 386-390
        • Cachon-Gonzalez M.B.
        • Fenner S.
        • Coffin J.M.
        • Moran C.
        • Best S.
        • Stoye J.P.
        Structure and expression of the hairless gene of mice.
        Proc Natl Acad Sci USA. 1994; 91: 7717-7721
        • Stoye J.P.
        • Fenner S.
        • Greenoak G.E.
        • Moran C.
        • Coffin J.M.
        Role of endogenous retroviruses as mutagens: the hairless mutation of mice.
        Cell. 1988; 54: 383-391
        • Potter G.B.
        • Beaudoin 3rd, G.M.
        • DeRenzo C.L.
        • Zarach J.M.
        • Chen S.H.
        • Thompson C.C.
        The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor.
        Genes Dev. 2001; 15: 2687-2701
        • Ahmad W.
        • Zlotogorski A.
        • Panteleyev A.A.
        • Lam H.
        • Ahmad M.
        • ul Haque M.F.
        • et al.
        Genomic organization of the human hairless gene (HR) and identification of a mutation underlying congenital atrichia in an Arab Palestinian family.
        Genomics. 1999; 1: 141-148
        • Sprecher E.
        • Bergman R.
        • Szargel R.
        • Friedman-Birnbaum R.
        • Cohen N.
        Identification of a genetic defect in the hairless gene in atrichia with papular lesions: evidence for phenotypic heterogeneity among inherited atrichias.
        Am J Hum Genet. 1999; 64: 1323-1329
        • Ahmad W.
        • Nomura K.
        • McGrath J.A.
        • Hashimoto I.
        • Christiano A.M.
        A homozygous nonsense mutation in the zinc-finger domain of the human hairless gene underlies congenital atrichia.
        J Invest Dermatol. 1999; 113: 281-283
        • Masse M.
        • Martinez-Mir A.
        • Lam H.
        • Geraghty M.T.
        • Christiano A.M.
        Identification of a recurrent mutation in the human hairless gene underlying atrichia with papular lesions.
        Clin Exp Dermatol. 2005; 30: 363-365
        • Betz R.C.
        • Indelman M.
        • Pforr J.
        • Schreiner F.
        • Bauer R.
        • Bergman R.
        • et al.
        Identification of mutations in the human hairless gene in two new families with congenital atrichia.
        Arch Dermatol Res. 2007; 299: 157-161
        • Zlotogorski A.
        • Panteleyev A.A.
        • Aita V.M.
        • Christiano A.M.
        Clinical and molecular diagnostic criteria of congenital atrichia with papular lesions.
        J Invest Dermatol. 2002; 118: 887-890
        • Kruse R.
        • Cichon S.
        • Anker M.
        • Hillmer A.M.
        • Barros-Nunez P.
        • Cantu J.M.
        • et al.
        Novel hairless mutations in two kindreds with autosomal recessive papular atrichia.
        J Invest Dermatol. 1999; 113: 954-959
        • Henn W.
        • Zlotogorski A.
        • Lam H.
        • Martinez-Mir A.
        • Zaun H.
        • Christiano A.M.
        Atrichia with papular lesions resulting from compound heterozygous mutations in the hairless gene: a lesson for differential diagnosis of alopecia universalis.
        J Am Acad Dermatol. 2002; 47: 519-523
        • Terracina M.
        • Posteraro P.
        • Schubert M.
        • Sonego G.
        • Atzori F.
        • Zambruno G.
        • et al.
        Compound heterozygosity for a recessive glycine substitution and a splice site mutation in the COL7A1 gene causes an unusually mild form of localized recessive dystrophic epidermolysis bullosa.
        J Invest Dermatol. 1998; 111: 744-750
        • Kon A.
        • McGrath J.A.
        • Pulkkinen L.
        • Nomura K.
        • Nakamura T.
        • Maekawa Y.
        • et al.
        Glycine substitution mutations in the type VII collagen gene (COL7A1) in dystrophic epidermolysis bullosa: implications for genetic counseling.
        J Invest Dermatol. 1997; 108: 224-228
        • Paller A.S.
        • Varigos G.
        • Metzker A.
        • Bauer R.C.
        • Opie J.
        • Martinez-Mir A.
        • et al.
        Compound heterozygous mutations in the hairless gene in atrichia with papular lesions.
        J Invest Dermatol. 2003; 121: 430-432
        • Wang J.
        • Malloy P.J.
        • Feldman D.
        Interactions of the vitamin D receptor with the corepressor hairless: analysis of hairless mutants in atrichia with papular lesions.
        J Biol Chem. 2007; 282: 25231-25239