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• W1997742178 abstract "human desmoglein 4 gene/protein localized autosomal recessive hypotrichosis TO THE EDITOR A newly defined form of inherited hair loss, named localized autosomal recessive hypotrichosis (LAH, OMIM 607903), was recently described in the literature and shown to be linked to chromosome 18 by us and others (Kljuic et al., 2003aKljuic A. Bazzi H. Sundberg J.P. Martinez-Mir A. O'Shaughnessy R. Mahoney M.G. 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; Rafique et al., 2003Rafique M.A. Ansar M. Jamal S.M. Malik S. Sohail M. Faiyaz-Ul-Haque M. et al.A locus for hereditary hypotrichosis localized to human chromosome 18q21.1.Eur J Hum Genet. 2003; 11: 623-628Crossref PubMed Scopus (31) Google Scholar). We first identified a large, intragenic deletion in the desmoglein 4 gene (DSG4) as the underlying mutation in two unrelated families of Pakistani origin (Kljuic et al., 2003aKljuic A. Bazzi H. Sundberg J.P. Martinez-Mir A. O'Shaughnessy R. Mahoney M.G. 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). This mutation and others have subsequently been found in other Pakistani families around the world (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; Rafiq et al., 2004Rafiq M.A. Ansar M. Mahmood S. Haque S. Faiyaz-ul-Haque M. Leal S.M. et al.A recurrent intragenic deletion mutation in DSG4 gene in three Pakistani families with autosomal recessive hypotrichosis.J Invest Dermatol. 2004; 123: 247-248Crossref PubMed Scopus (33) Google Scholar; John et al., 2006John P. Tariq M. Arshad Rafiq M. Amin-Ud-Din M. Muhammad D. Waheed I. et al.Recurrent intragenic deletion mutation in desmoglein 4 gene underlies autosomal recessive hypotrichosis in two Pakistani families of Balochi and Sindhi origins.Arch Dermatol Res. 2006; 298: 135-137Crossref PubMed Scopus (21) Google Scholar). Additionally, other mutations have been identified in patients who have monilethrix hairs as part of their phenotypic presentation (Schaffer et al., 2006Schaffer J.V. Bazzi H. Vitebsky A. Witkiewicz A. Kovich O.I. Kamino H. et al.Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions.J Invest Dermatol. 2006; 126: 1286-1291Crossref PubMed Scopus (58) Google Scholar; Schweizer, 2006Schweizer J. More than one gene involved in monilethrix: intracellular but also extracellular players.J Invest Dermatol. 2006; 126: 1216-1219Crossref PubMed Scopus (26) Google Scholar; Shimomura et al., 2006Shimomura Y. Sakamoto F. Kariya N. Matsunaga K. Ito M. Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis.J Invest Dermatol. 2006; 126: 1281-1285Crossref PubMed Scopus (56) Google Scholar; Zlotogorski et al., 2006Zlotogorski A. Marek D. Horev L. Abu A. Ben-Amitai D. Gerad L. et al.An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis.J Invest Dermatol. 2006; 126: 1292-1296Crossref PubMed Scopus (62) Google Scholar) that have begun to broaden our understanding of the genotype–phenotype relationships within LAH. LAH typically affects the scalp, trunk, and extremities, largely sparing the facial, pubic, and axillary hair. Typical hairs are fragile and break easily, leaving short sparse scalp hairs with a characteristic appearance. Using comparative genomics, we also demonstrated that human LAH is allelic with the lanceolate hair (lah) mouse (Kljuic et al., 2003aKljuic A. Bazzi H. Sundberg J.P. Martinez-Mir A. O'Shaughnessy R. Mahoney M.G. 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), as well as the lah rat phenotype (Jahoda et al., 2004Jahoda C.A. Kljuic A. O'Shaughnessy R. Crossley N. Whitehouse C.J. Robinson M. 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; Bazzi et al., 2004Bazzi H. Kljuic A. Christiano A.M. 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; Meyer et al., 2004Meyer B. Bazzi H. Zidek V. Musilova A. Pravenec M. Kurtz T.W. 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 DSG4 underlying LAH in humans, and to gain an appreciation of the variation in clinical phenotype among affected individuals, we are performing molecular analysis of DSG4 in families from around the world. Here, we describe a large consanguineous family of Pakistani origin with four males and two females affected with LAH with varying degrees of phenotypic severity (Figure 1a and b, Figure S1a and b). All affected children were born without hair and hairs were ritually shaved at approximately 3 weeks of age. Subsequently, sparse, coarse hair growth occurred and was sometimes accompanied by itching, redness, and roughness of the scalp. Fragile hairs were present in all affected individuals (Figure 1, Figure S1). All children are otherwise healthy and developing normally. Download .gif (.03 MB) Help with files Supplementary Figure S1 A comparison of the clinical findings of the four male individuals revealed marked variability within the family that is not age-dependent in terms of severity. Individuals V-4, V-1, V-6, and VI-1 were 5, 7, 13, and 17 years of age at the time of examination (Figure 1a,b, Figure S1a and b, Figure 2a). V-4 and V-1 display a relatively mild sparse hair phenotype, with stiff, sparse, coarse, brittle hair with sparing of the eyebrows and lashes (Figure 1a). In contrast, VI-6, 17 years of age, presented with sparse and brittle hair, follicular hyperkeratosis, erythema, and scaling affecting particularly the scalp, as well as the eyebrows and eyelashes (Figure 1b, Figure S1b). Finally, individual V-6, 13 years of age, is almost completely without hair, and exhibits the most extreme phenotype within the family (Figure 1b, Figure S1a). Plucked hair fibers from affected individuals revealed the presence of abnormally broken hairs and tapered ends, as well as occasional swellings in the hair shaft (Figure 1c and d, Figure S1c and d). In all affected individuals, the skin is otherwise normal with no papular lesions on the limbs, and no palmoplantar keratoderma. Sweating, teeth, and nails are normal and no beaded monilethrix hairs were observed in these individuals. Despite the marked variation in severity, the clinical findings are most consistent with a diagnosis of localized autosomal recessive hypotrichosis. We obtained DNA from the six affected individuals and 12 unaffected individuals from the family. 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, NY1989Google Scholar). All samples were collected following informed consent, under institutional approval and in adherence to the Declaration of Helsinki Principles. 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, CA), following purification in Centriflex™ Gel Filtration Cartridges (Edge Biosystems, Gaithersburg, MD) as we described earlier (Kljuic et al., 2003aKljuic A. Bazzi H. Sundberg J.P. Martinez-Mir A. O'Shaughnessy R. Mahoney M.G. 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. We identified a single nucleotide deletion within exon 3, designated 87delG (Figure 2b). This results in a frameshift and premature termination codon 162 bp downstream of the deletion. The resulting nonsense-bearing mRNA transcript will likely be degraded via nonsense-mediated mRNA decay (Khajavi et al., 2006Khajavi M. Inoue K. Lupski J.R. Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease.Eur J Hum Genet. 2006; 14: 1074-1081Crossref PubMed Scopus (261) Google Scholar) leading to a presumable absence of functional DSG4 protein in affected individuals. This is predicted to result in a null mutation in DSG4, comparable to the lahJ/lahJ mouse (Kljuic et al., 2003aKljuic A. Bazzi H. Sundberg J.P. Martinez-Mir A. O'Shaughnessy R. Mahoney M.G. 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 Iffa–Credo and SH rats (Bazzi et al., 2004Bazzi H. Kljuic A. Christiano A.M. 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; Meyer et al., 2004Meyer B. Bazzi H. Zidek V. Musilova A. Pravenec M. Kurtz T.W. 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), which have an absence of Dsg4 mRNA. All but one of the previously reported mutations in Pakistani families have involved a recurrent in-frame deletion of exons 5–8, removing amino acids 125–335 (Kljuic et al., 2003aKljuic A. Bazzi H. Sundberg J.P. Martinez-Mir A. O'Shaughnessy R. Mahoney M.G. 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; 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; Rafiq et al., 2004Rafiq M.A. Ansar M. Mahmood S. Haque S. Faiyaz-ul-Haque M. Leal S.M. et al.A recurrent intragenic deletion mutation in DSG4 gene in three Pakistani families with autosomal recessive hypotrichosis.J Invest Dermatol. 2004; 123: 247-248Crossref PubMed Scopus (33) Google Scholar; John et al., 2006John P. Tariq M. Arshad Rafiq M. Amin-Ud-Din M. Muhammad D. Waheed I. et al.Recurrent intragenic deletion mutation in desmoglein 4 gene underlies autosomal recessive hypotrichosis in two Pakistani families of Balochi and Sindhi origins.Arch Dermatol Res. 2006; 298: 135-137Crossref PubMed Scopus (21) Google Scholar). These amino acids correspond to part of the EC1 domain, all of EC2 and the beginning of the EC3 domain. These regions of DSG4 are believed to be critical in cadherin–cadherin interaction and dimerization (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 (512) Google Scholar), which is necessary for proper cell–cell adhesion. Missense mutations in this same region have been demonstrated in the lah/lah mouse (Kljuic et al., 2003aKljuic A. Bazzi H. Sundberg J.P. Martinez-Mir A. O'Shaughnessy R. Mahoney M.G. 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. Crossley N. Whitehouse C.J. Robinson M. 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). Additionally, we have recently identified a missense mutation in the R-A-L cadherin interaction site of DSG4 in a family of Iraqi origin (Messenger et al., 2005Messenger A.G. Bazzi H. Parslew R. Shapiro L. Christiano A.M. A missense mutation in the cadherin interaction site of the desmoglein 4 gene underlies localized autosomal recessive hypotrichosis.J Invest Dermatol. 2005; 125: 1077-1079Crossref PubMed Scopus (26) Google Scholar). We and others recently described the presence of monilethrix-like hairs in LAH patients from different ethnic origins (Schaffer et al., 2006Schaffer J.V. Bazzi H. Vitebsky A. Witkiewicz A. Kovich O.I. Kamino H. et al.Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions.J Invest Dermatol. 2006; 126: 1286-1291Crossref PubMed Scopus (58) Google Scholar; Shimomura et al., 2006Shimomura Y. Sakamoto F. Kariya N. Matsunaga K. Ito M. Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis.J Invest Dermatol. 2006; 126: 1281-1285Crossref PubMed Scopus (56) Google Scholar; Zlotogorski et al., 2006Zlotogorski A. Marek D. Horev L. Abu A. Ben-Amitai D. Gerad L. et al.An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis.J Invest Dermatol. 2006; 126: 1292-1296Crossref PubMed Scopus (62) Google Scholar). Dominantly inherited monilethrix (OMIM 158000) is caused by mutations in hair shaft keratins (reviewed by Schweizer, 2006Schweizer J. More than one gene involved in monilethrix: intracellular but also extracellular players.J Invest Dermatol. 2006; 126: 1216-1219Crossref PubMed Scopus (26) Google Scholar), and since DSG4 is a desmosomal protein mainly expressed in the cortex of the hair shaft (Bazzi et al., 2006Bazzi H. Getz A. Mahoney M.G. Ishida-Yamamoto A. Langbein L. Wahl J.K. et al.Desmoglein 4 is expressed in highly differentiated keratinocytes and trichocytes in human epidermis and hair follicle.Differentiation. 2006; 74: 129-140Crossref PubMed Scopus (73) Google Scholar; Mahoney et al., 2006Mahoney M.G. Hu Y. Brennan D. Bazzi H. Christiano A.M. Wahl J.K. Delineation of diversified desmoglein distribution in stratified squamous epithelia: implications in diseases.Exp Dermatol. 2006; 15: 101-109Crossref PubMed Scopus (61) Google Scholar), it is likely that DSG4 is directly associated or linked to hair shaft keratins, although this has yet to be demonstrated experimentally. Despite the distinct patterns of inheritance, it is perhaps not surprising that LAH and monilethrix share the common phenotypic features of a periodically uneven diameter as well as stiffness and brittleness of the hair shaft. Interestingly, DSG4 is the only desmosomal cadherin to date, which has been associated with a human hair phenotype (Huber, 2003Huber O. Structure and function of desmosomal proteins and their role in development and disease.Cell Mol Life Sci. 2003; 60: 1872-1890Crossref PubMed Scopus (90) Google Scholar; McGrath and Wessagowit, 2005McGrath J.A. Wessagowit V. Human hair abnormalities resulting from inherited desmosome gene mutations.Keio J Med. 2005; 54: 72-79Crossref PubMed Scopus (20) Google Scholar). No human diseases have been described resulting from mutations in desmocollins, and the dominant mutations identified in DSG1 result in striate palmoplantar keratoderma (OMIM 148700), characterized by thickening of the skin on palms and soles, but no hair involvement (Rickman et al., 1999Rickman L. Simrak D. Stevens H.P. Hunt D.M. King I.A. Bryant S.P. et al.N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma.Hum Mol Genet. 1999; 8: 971-976Crossref PubMed Scopus (172) Google Scholar; Kljuic et al., 2003bKljuic A. Gilead L. Martinez-Mir A. Frank J. Christiano A.M. Zlotogorski A. A nonsense mutation in the desmoglein 1 gene underlies striate keratoderma.Exp Dermatol. 2003; 12: 523-527Crossref PubMed Scopus (40) Google Scholar). Recently, mutations in DSG2 were identified in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), an autosomal dominant disorder characterized by fibro-fatty replacement of cardiac myocytes in the right ventricle, but without a hair phenotype (Awad et al., 2006Awad M.M. Dalal D. Cho E. Amat-Alarcon N. James C. Tichnell C. et al.DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy.Am J Hum Genet. 2006; 79: 136-142Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar; Pilichou et al., 2006Pilichou K. Nava A. Basso C. Beffagna G. Bauce B. Lorenzon A. et al.Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy.Circulation. 2006; 113: 1171-1179Crossref PubMed Scopus (424) Google Scholar). Furthermore, no human mutations have been found in the DSG3 gene although mutations in the mouse Dsg3 result in the balding phenotype, characterized by cyclical hair loss (Koch et al., 1997Koch P.J. Mahoney M.G. Ishikawa H. Pulkkinen L. Uitto J. Shultz L. et al.Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris.J Cell Biol. 1997; 137: 1091-1102Crossref PubMed Scopus (362) Google Scholar; Pulkkinen et al., 2002Pulkkinen L. Choi Y.W. Simpson A. Montagutelli X. Sundberg J. Uitto J. et al.Loss of cell adhesion in Dsg3bal-Pas mice with homozygous deletion mutation (2079del14) in the desmoglein 3 gene.J Invest Dermatol. 2002; 119: 1237-1243Crossref PubMed Scopus (31) Google Scholar). To our knowledge, the patients described in this report represent the first example of a null mutation of DSG4 in humans with LAH. The phenotype in this family, albeit variable, is no more severe than individuals with LAH resulting from other types of homozygous mutations, including the recurrent intragenic deletion (Kljuic et al., 2003aKljuic A. Bazzi H. Sundberg J.P. Martinez-Mir A. O'Shaughnessy R. Mahoney M.G. 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; 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; Rafiq et al., 2004Rafiq M.A. Ansar M. Mahmood S. Haque S. Faiyaz-ul-Haque M. Leal S.M. et al.A recurrent intragenic deletion mutation in DSG4 gene in three Pakistani families with autosomal recessive hypotrichosis.J Invest Dermatol. 2004; 123: 247-248Crossref PubMed Scopus (33) Google Scholar; John et al., 2006John P. Tariq M. Arshad Rafiq M. Amin-Ud-Din M. Muhammad D. Waheed I. et al.Recurrent intragenic deletion mutation in desmoglein 4 gene underlies autosomal recessive hypotrichosis in two Pakistani families of Balochi and Sindhi origins.Arch Dermatol Res. 2006; 298: 135-137Crossref PubMed Scopus (21) Google Scholar), the cadherin-interaction site (Messenger et al., 2005Messenger A.G. Bazzi H. Parslew R. Shapiro L. Christiano A.M. A missense mutation in the cadherin interaction site of the desmoglein 4 gene underlies localized autosomal recessive hypotrichosis.J Invest Dermatol. 2005; 125: 1077-1079Crossref PubMed Scopus (26) Google Scholar), or compound heterozygous for two different types of mutations (Schaffer et al., 2006Schaffer J.V. Bazzi H. Vitebsky A. Witkiewicz A. Kovich O.I. Kamino H. et al.Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions.J Invest Dermatol. 2006; 126: 1286-1291Crossref PubMed Scopus (58) Google Scholar; Shimomura et al., 2006Shimomura Y. Sakamoto F. Kariya N. Matsunaga K. Ito M. Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis.J Invest Dermatol. 2006; 126: 1281-1285Crossref PubMed Scopus (56) Google Scholar; Zlotogorski et al., 2006Zlotogorski A. Marek D. Horev L. Abu A. Ben-Amitai D. Gerad L. et al.An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis.J Invest Dermatol. 2006; 126: 1292-1296Crossref PubMed Scopus (62) Google Scholar). The wide variation in phenotype within affected members of the family in this report, who are each homozygous for the same deletion mutation, 87delG, correlates with the variable inter- and intra-familial involvement mentioned by Zlotogorski et al., 2006Zlotogorski A. Marek D. Horev L. Abu A. Ben-Amitai D. Gerad L. et al.An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis.J Invest Dermatol. 2006; 126: 1292-1296Crossref PubMed Scopus (62) Google Scholar. It is also of interest that moniliform hairs were found in most (but not all) families reported by us (Kljuic et al., 2003aKljuic A. Bazzi H. Sundberg J.P. Martinez-Mir A. O'Shaughnessy R. Mahoney M.G. 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; 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; Messenger et al., 2005Messenger A.G. Bazzi H. Parslew R. Shapiro L. Christiano A.M. A missense mutation in the cadherin interaction site of the desmoglein 4 gene underlies localized autosomal recessive hypotrichosis.J Invest Dermatol. 2005; 125: 1077-1079Crossref PubMed Scopus (26) Google Scholar; Schaffer et al., 2006Schaffer J.V. Bazzi H. Vitebsky A. Witkiewicz A. Kovich O.I. Kamino H. et al.Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions.J Invest Dermatol. 2006; 126: 1286-1291Crossref PubMed Scopus (58) Google Scholar) and described in many (but not all) families reported by others (Rafiq et al., 2004Rafiq M.A. Ansar M. Mahmood S. Haque S. Faiyaz-ul-Haque M. Leal S.M. et al.A recurrent intragenic deletion mutation in DSG4 gene in three Pakistani families with autosomal recessive hypotrichosis.J Invest Dermatol. 2004; 123: 247-248Crossref PubMed Scopus (33) Google Scholar; John et al., 2006John P. Tariq M. Arshad Rafiq M. Amin-Ud-Din M. Muhammad D. Waheed I. et al.Recurrent intragenic deletion mutation in desmoglein 4 gene underlies autosomal recessive hypotrichosis in two Pakistani families of Balochi and Sindhi origins.Arch Dermatol Res. 2006; 298: 135-137Crossref PubMed Scopus (21) Google Scholar; Shimomura et al., 2006Shimomura Y. Sakamoto F. Kariya N. Matsunaga K. Ito M. Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis.J Invest Dermatol. 2006; 126: 1281-1285Crossref PubMed Scopus (56) Google Scholar; Zlotogorski et al., 2006Zlotogorski A. Marek D. Horev L. Abu A. Ben-Amitai D. Gerad L. et al.An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis.J Invest Dermatol. 2006; 126: 1292-1296Crossref PubMed Scopus (62) Google Scholar). Additional hair shaft abnormalities similar to those in monilethrix have been reported in humans and mice carrying mutations in DSG4 (Sundberg et al., 2000Sundberg J.P. Boggess D. Bascom C. Limberg B.J. Shultz L.D. Sundberg B.A. et al.Lanceolate hair-J (lahJ): a mouse model for human hair disorders.Exp Dermatol. 2000; 9: 206-218Crossref PubMed Scopus (35) Google Scholar; Zlotogorski et al., 2006Zlotogorski A. Marek D. Horev L. Abu A. Ben-Amitai D. Gerad L. et al.An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis.J Invest Dermatol. 2006; 126: 1292-1296Crossref PubMed Scopus (62) Google Scholar). These findings suggest that LAH and recessively inherited monilethrix are related conditions and part of a spectrum with variable expressivity. The variations in inter- and intra-familial findings indicate that mutations in DSG4 may present with a different clinical picture due to potential modifying genes among familial cases, or different types/combinations of mutations between families. The authors state no conflict of interest. We appreciate the participation of the family members in this study. This study was supported in part by grants USPHS NIH R01-AR44924 (AMC). Figure S1. Close up of the scalp of affected individuals and the abnormal hair shafts. Download .doc (.02 MB) Help with doc files Legend to Supplementary Figure S1" @default.
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• W1997742178 date "2007-07-01" @default.
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• W1997742178 title "Localized Autosomal Recessive Hypotrichosis Due to a Frameshift Mutation in the Desmoglein 4 Gene Exhibits Extensive Phenotypic Variability within a Pakistani Family" @default.
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