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• W2029265147 abstract "human desmoglein 4 gene/protein localized autosomal recessive hypotrichosis To the Editor: We recently described a novel form of hair loss, termed localized autosomal recessive hypotrichosis (LAH, OMIM 607903), which is a rare, autosomal recessive disorder affecting the scalp, trunk and extremities, and largely sparing the facial, pubic and axillary hair (Kljuic et al., 2003Kljuic A. Bazzi H. Sundberg J.P. et al.Desmoglein 4 in hair follicle differentiation and epidermal adhesion: Evidence from inherited hypotrichosis and acquired pemphigus vulgaris.Cell. 2003; 113: 249-260Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). Typical hairs are fragile and break easily, leaving short sparse scalp hairs with a characteristic appearance. We and others reported linkage of LAH to chromosome 18, in the region of the desmosomal cadherin gene cluster (Kljuic et al., 2003Kljuic A. Bazzi H. Sundberg J.P. et al.Desmoglein 4 in hair follicle differentiation and epidermal adhesion: Evidence from inherited hypotrichosis and acquired pemphigus vulgaris.Cell. 2003; 113: 249-260Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar; Rafiq et al., 2003Rafiq M.A. Ansar M. Jamal S.M. et al.A locus for hereditary hypotrichosis localized to human chromosome 18q21.Eur J Hum Genet. 2003; 11: 623-628Crossref PubMed Scopus (31) Google Scholar), in which we discovered a novel member of this gene family, known as desmoglein 4 (Kljuic et al., 2003Kljuic A. Bazzi H. Sundberg J.P. et al.Desmoglein 4 in hair follicle differentiation and epidermal adhesion: Evidence from inherited hypotrichosis and acquired pemphigus vulgaris.Cell. 2003; 113: 249-260Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). We first identified a large, intragenic deletion of exons 5–8 in the desmoglein 4 gene as the underlying mutation in two unrelated families of Pakistani origin (Kljuic et al., 2003Kljuic A. Bazzi H. Sundberg J.P. et al.Desmoglein 4 in hair follicle differentiation and epidermal adhesion: Evidence from inherited hypotrichosis and acquired pemphigus vulgaris.Cell. 2003; 113: 249-260Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar), which was then subsequently reported in a total of five additional Pakistani families by our group (Moss et al., 2004Moss C. Martinez-Mir A. Lam H. Tadin-Strapps M. Kljuic A. Christiano A.M. A recurrent intragenic deletion in the desmoglein 4 gene underlies localized autosomal recessive hypotrichosis.J Invest Dermatol. 2004; 123: 607-610Crossref PubMed Scopus (32) Google Scholar) and others (Rafiq et al., 2004Rafiq M.A. Ansar M. Mahmood S. et al.A recurrent intragenic deletion mutation in DS64 gene in three Pakistani families with autosomal recessive hypotrichosis.J Invest Dermatol. 2004; 123: 247-248Crossref PubMed Scopus (33) Google Scholar), suggesting widespread dispersion of this chromosome. Using comparative genomics, we also demonstrated that human LAH is allelic with both lanceolate hair (lah and lahJ) mouse mutations (Kljuic et al., 2003Kljuic A. Bazzi H. Sundberg J.P. et al.Desmoglein 4 in hair follicle differentiation and epidermal adhesion: Evidence from inherited hypotrichosis and acquired pemphigus vulgaris.Cell. 2003; 113: 249-260Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). More recently, we identified three independent rat mutations with the lanceolate hair (lah) phenotype (Bazzi et al., 2004Bazzi H. Kljuic A. Christiano A.M. Panteleyev A.A. Intragenic deletion in the Desmoglein 4 gene underlies the skin phenotype in the Iffa Credo “hairless” rat.Differentiation. 2004; 72: 450-464Crossref PubMed Scopus (24) Google Scholar; Jahoda et al., 2004Jahoda C.A. Kljuic A. O'Shaughnessy R. et al.The lanceolate hair rat phenotype results from a missense mutation in a calcium coordinating site of the desmoglein 4 gene.Genomics. 2004; 83: 747-756Crossref PubMed Scopus (43) Google Scholar; Meyer et al., 2004Meyer B. Bazzi H. Zidek V. et al.A spontaneous mutation in the desmoglein 4 gene underlies hypotrichosis in a new lanceolate hair rat model.Differentiation. 2004; 72: 541-547Crossref PubMed Scopus (26) Google Scholar). In order to expand the allelic series of mutations in the desmoglein 4 gene underlying LAH in humans, we have undertaken a molecular analysis of the DSG4 gene in suspected LAH affected families from around the world. Here, we report a family of Iraqi origin with one child affected with LAH (Figure 1). The affected 5-y-old girl has one 6-y-old brother with normal hair (Figure 1e). Their parents are first cousins of Iraqi origin, are unaffected (Figure 1e) and have no family history of other hair disorders. The affected child was born without hair and was not ritually shaved. Subsequently, sparse coarse hair growth was accompanied by itching, redness and roughness of the scalp, which showed prominent follicular hyperkeratosis (Figure 1a, b). The hair shafts were marked by terminal fractures and trichorrhexis nodosa but no other specific abnormalities, and hair amino acid analysis was normal. At the age of 2 mo, the proband showed complete alopecia with follicular prominence on the scalp. By 15 mo, there was sparse, coarse, brittle hair with follicular hyperkeratosis, erythema and scaling affecting particularly the scalp, but also eyebrows and eyelashes. Now aged 5, the girl's scalp hair remains sparse and is clearly brittle, less than 1cm long at sites of friction and up to 8 cm in other areas. She now has marked follicular hyperkeratosis on the extensor aspects of the limbs. The skin is otherwise normal with no papular lesions on the limbs, and no palmoplantar keratoderma. Sweating, teeth and nails appear normal. Overall, the clinical findings are most consistent with a diagnosis of LAH. We obtained blood samples from the two children and both parents. Genomic DNA was isolated from peripheral blood collected in EDTA-containing tubes according to standard techniques (Sambrook et al., 1989Sambrook J. Fritsch E.F. Maniatis T. Molecular Cloning: A Laboratory Manual. 2nd edn. Cold Spring Harbor Laboratory Press, New York, USA1989Google Scholar). All samples were collected following informed written consent of the subjects and the study was conducted in accordance with protocols approved by the Institutional Review Board (IRB) of Columbia University and the Declaration of Helsinki Guidelines. To screen for a mutation in the human DSG4 gene, all exons and splice junctions were PCR amplified from genomic DNA and sequenced directly in an ABI Prism 310 Automated Sequencer, using the ABI Prism Big Dye Terminator Cycle Sequencing Ready Reaction Kit (PE Applied Biosystems, Foster City, California), following purification in Centriflex Gel Filtration Cartridges (Edge Biosystems, Gaithersburg, Maryland) as we described earlier (Kljuic et al., 2003Kljuic A. Bazzi H. Sundberg J.P. et al.Desmoglein 4 in hair follicle differentiation and epidermal adhesion: Evidence from inherited hypotrichosis and acquired pemphigus vulgaris.Cell. 2003; 113: 249-260Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). The mutation was identified by visual inspection and comparison with control sequences generated from unrelated, unaffected individuals (Figure 2a). We identified a homozygous tandem dinucleotide transversion mutation in the affected proband, which changed the GG at nucleotide positions 384–385 to a TT dinucleotide (Figure 2a). Both parents were heterozygous carriers of this mutation, and the unaffected brother was genetically normal. To exclude the possibility that this mutation represents a polymorphism, we screened a panel of seventy unrelated, unaffected individuals. Since the mutation destroys an NciI restriction site, we digested the PCR products of exon 5 with NciI and confirmed the absence of the variant from this representative sample of 140 chromosomes (data not shown). The first G at nucleotide 384 occurs in the third base of arginine codon 128, and is therefore a silent mutation (CGG to CGT). The second G at nucleotide 385, however, occurs in the first base of the neighboring alanine codon 129, resulting in the substitution of alanine by serine (GCT to TCT). This missense mutation, designated A129S, occurs within the cadherin interaction sequence R-A-L, and converts it to R-S-L. This region of DSG4 is thought to be critical for cadherin–cadherin dimerization interactions between cells based on data from classical cadherins (Boggon et al., 2002Boggon T.J. Murray J. Chappuis-Flament S. Wong E. Gumbiner B.M. Shapiro L. C-cadherin ectodomain structure and implications for cell adhesion mechanisms.Science. 2002; 296: 1308-1313Crossref PubMed Scopus (513) Google Scholar; Patel et al., 2003Patel S.D. Chen C.P. Bahna F. Honig B. Shapiro L. Cadherin-mediated cell–cell adhesion: Sticking together as a family.Curr Opin Struct Biol. 2003; 13: 690-698Crossref PubMed Scopus (162) Google Scholar) and is thus predicted to be essential for cell–cell adhesion. Cadherins present on the surface of opposing cells must dimerize in order to mediate adhesion. X-ray crystallography experiments have revealed the atomic-level mechanism of adhesion for type I cadherins, which interact by swapping the N-terminal β-strand between partner EC1 domains. Of note, all critical residues for these interactions, including A129 of DSG4 (Figure 2b), are conserved between the classical and desmosomal cadherins (Patel et al., 2003Patel S.D. Chen C.P. Bahna F. Honig B. Shapiro L. Cadherin-mediated cell–cell adhesion: Sticking together as a family.Curr Opin Struct Biol. 2003; 13: 690-698Crossref PubMed Scopus (162) Google Scholar). The side chain of Trp 2, within the swapped β-strand, serves as a key anchoring residue which becomes buried in a core pocket of the partner that is lined by residues A78 and A80 (numbering for the mature N-cadherin; Figure 2c) where the latter corresponds to the position of the A129S mutation in DSG4. The small size of the alanine side chain, and its hydrophobic character, are important for interactions with the Trp 2 side chain from its adhesive partner. Thus, we predict that the mutation A129S, which introduces a hydrophilic serine side chain might abrogate or negatively impact adhesive function. Indeed, site-directed mutagenesis of the corresponding alanine residue of N-cadherin (Figure 2b) to methionine has been shown to completely abrogate adhesion (Tamura et al., 1998Tamura K. Shan W.S. Hendrickson W.A. Colman D.R. Shapiro L. Structure–function analysis of cell adhesion by neural (N-) cadherin.Neuron. 1998; 20: 1153-1163Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar). Moreover, missense mutations in this same region have recently been demonstrated in the lah/lah mouse (Kljuic et al., 2003Kljuic A. Bazzi H. Sundberg J.P. et al.Desmoglein 4 in hair follicle differentiation and epidermal adhesion: Evidence from inherited hypotrichosis and acquired pemphigus vulgaris.Cell. 2003; 113: 249-260Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar) and the lah/lah rat (Jahoda et al., 2004Jahoda C.A. Kljuic A. O'Shaughnessy R. et al.The lanceolate hair rat phenotype results from a missense mutation in a calcium coordinating site of the desmoglein 4 gene.Genomics. 2004; 83: 747-756Crossref PubMed Scopus (43) Google Scholar), which are believed to disrupt the DSG4 interaction interface and lead to a similar ultrastructural defect observed in the torn desmosomes of the epidermis of the Dsg4 null lahJ mouse (Kljuic et al., 2003Kljuic A. Bazzi H. Sundberg J.P. et al.Desmoglein 4 in hair follicle differentiation and epidermal adhesion: Evidence from inherited hypotrichosis and acquired pemphigus vulgaris.Cell. 2003; 113: 249-260Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). The identification of A129S in this family represents the first mutation in human LAH that is distinct from the common Pakistani deletion allele of exons 5–8. Since the patients identified to date present with very similar clinical features, our findings suggest that raising the awareness of LAH as a differential diagnosis for hypotrichosis will reveal additional cases and further define an allelic series of mutations in human DSG4 in addition to the existing mouse and rat models (Meyer et al., 2004Meyer B. Bazzi H. Zidek V. et al.A spontaneous mutation in the desmoglein 4 gene underlies hypotrichosis in a new lanceolate hair rat model.Differentiation. 2004; 72: 541-547Crossref PubMed Scopus (26) Google Scholar). We appreciate the participation of the family members in this study. We appreciate the excellent technical assistance of Helen Lam and Susan White. This study was supported in part by grants USPHS NIH R01-AR44924 (A. M. C.) and NIH R01GM062270–05 (L. S.)." @default.
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• W2029265147 title "A Missense Mutation in the Cadherin Interaction Site of The Desmoglein 4 Gene Underlies Localized Autosomal Recessive Hypotrichosis" @default.
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