Mutations in the Desmoglein 4 Gene Underlie Localized Autosomal Recessive Hypotrichosis with Monilethrix Hairs and Congenital Scalp Erosions

Department of Dermatology, New York University School of Medicine, New York, NY, USA.
Journal of Investigative Dermatology (Impact Factor: 7.22). 07/2006; 126(6):1286-91. DOI: 10.1038/sj.jid.5700237
Source: PubMed


Localized autosomal recessive hypotrichosis (LAH) is a recently defined disorder characterized by fragile, short, sparse hairs on the scalp, trunk, and extremities. Mutations in desmoglein 4 (DSG4), a novel member of the desmosomal cadherin family that is expressed in the hair follicle as well as the suprabasal epidermis, have been found to underlie LAH. Thus far, the allelic series includes a recurrent intragenic deletion identified in affected Pakastani kindreds and a missense mutation detected in an Iraqi family. We report three siblings of Iraqi and Iranian origin with LAH that presented with congenital scalp erosions and monilethrix-like hairs, features that have not been previously described in this disorder. Follicular hyperkeratotic papules and marked pruritus were also prominent clinical findings. Novel compound heterozygous DSG4 mutations, including a splice-site mutation and a missense mutation that disrupts a conserved calcium-binding site in the extracellular (EC)2-EC3 interface, were found to underlie the disease in this family. These observations broaden the phenotypic and genotypic spectrum of LAH, further illustrating the consequences of DSG4 dysfunction on epidermal and hair shaft integrity.

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    • "More recently, DSG4 gene mutations were found to be associated with human monilethrix hairs (Shimomura et al., 2006; Amagai, 2010). These studies convincingly demonstrate that DSG4 plays an important role in regulating the proliferation and differentiation of hair follicles in mammals (Schaffer et al., 2006; El-Amraoui and Petit, 2010). Although our knowledge about the sheep DSG4 gene remains limited, some DNA sequences of sheep that are homologous to this gene in other organisms are available in the GenBank. "
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    ABSTRACT: The desmoglein 4 (DSG4) gene is a potential candidate in the search for genes that may affect wool traits, because of its function. This study aimed to screen for polymorphisms in partial exon 16 and 3ꞌUTR of the sheep desmoglein 4 DSG4 gene, and to test its possible association with wool length and crimp associated with fur. Overall, 326 sheep were scanned via single-strand conformational polymorphism assay, through three pairs of primers. The breeds included Tan, Han, and TanxHan from China, Polled Dorset from Australia, and Suffolk from Britain genotypes AA, BB, and AB for primer2 and genotypes DD, EE, and DE for primer3 were detected in native breeds. Six SNPs and 3-bp insertion/deletions were found in exon 16, of which 4 lead to amino acid substitutions. In addition, 1 SNP was found in 3ꞌUTR. The DSG4 genotype was found to be strongly associated with all wool traits that were considered in this study (P < 0.01). Sheep with the genotype MM had a higher least square mean compared to sheep with the genotype WW or WM with respect to birth scapular wool length (P < 0.01), crimp number of birth scapular wool crimp (P < 0.01), crimp number of weaning scapular wool crimp (P < 0.01), and crimp number of weaning rump wool crimp (P < 0.01, P < 0.05). In conclusion, our study is the first to demonstrate that the DSG4 gene may be a candidate, or major gene, which influences important wool traits.
    Full-text · Article · Jul 2014 · Genetics and molecular research: GMR
    • "Desmoglein 4 mutations are mapped to the chromosome 3q with a deletion in EX5-8del, causing a localized autosomal recessive hypotrichosis.[13] Localized autosomal recessive hypothrichosis is a recently defined disorder characterized clinically with sparse hair in the scalp, chest, arms, and legs, but sparing of the axillary and pubic hair and eyelashes. "
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    ABSTRACT: The desmosomes form the basis of intercellular support structure within the epidermis. However, various junctions, including gap junctions, adherens junctions, and tight junctions play an important part in the intercellular bridges that are vital for cell-cell interactions and structural stability. Numerous mutations can affect the genetic structure that make up these junctions and in turn cause disease. Most of these conditions have hair abnormalities and this article will briefly elucidate the various manifestations in the hair. As these junctional elements are found in other organs like the heart, liver, and eye, there could be serious systemic associations along with the hair changes.
    No preview · Article · Mar 2009 · International Journal of Trichology
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    • "Collectively, these findings suggest that the phenotypes resulted from P2RY5 and LIPH mutations significantly overlap , and both mutations can show variable phenotypes from WH to sparse hair. We and others have previously reported the same phenomenon of overlap between hypotrichosis and monilethrix (Kljuic et al., 2003; Shimomura et al., 2006; Schaffer et al., 2006; Zlotogorski et al., 2006). Such observations emphasize the wide variability in the expression of hair phenotypes between different individuals (Schweizer, 2006; Sprecher, 2008). "
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    ABSTRACT: Woolly hair (WH) is characterized by the presence of fine and tightly curled hair. WH can appear as a symptom of some systemic diseases, or without associated findings (nonsyndromic WH). Nonsyndromic WH is known to be inherited as either an autosomal-dominant (OMIM 194300) or recessive (ARWH; OMIM 278150) trait. In this study, we identified 11 consanguineous families of Pakistani origin with ARWH, as well as associated features including sparse and hypopigmented hair shafts. We first checked for mutations in the P2RY5 gene, which encodes an orphan G-protein-coupled receptor that we recently identified as a cause of ARWH. However, none of the 11 families had mutations in the P2RY5 gene. To identify the disease locus, we performed linkage studies in one of these families using the Affymetrix 10K array, and identified a region of suggestive linkage on chromosome 3q27. This region contains the lipase H (LIPH) gene which has been recently shown to underlie an autosomal-recessive form of hypotrichosis. Mutation analysis resulted in the identification of a total of 5 pathogenic mutations in the LIPH of all 11 families analyzed. These results show that LIPH is a second causative gene for ARWH/hypotrichosis, giving rise to a phenotype clinically indistinguishable from P2RY5 mutations.
    Full-text · Article · Nov 2008 · Journal of Investigative Dermatology
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