A Recurrent Intragenic Deletion in the Desmoglein 4 Gene Underlies Localized Autosomal Recessive Hypotrichosis

6 páginas, 2 figuras.A newly defined form of inherited hair loss, named localized autosomal recessive hypotrichosis (LAH, OMIM 607903), was recently described in the literature (Kljuic et al. 2003a; Rafique et al. 2003) and shown to be linked to chromosome 18. We 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. 2003a). LAH is an autosomal recessive form of hypotrichosis affecting the scalp, trunk, and extremities, and 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. 2003a), as well as the lanceolate hair (lah) rat phenotype (Jahoda et al. 2004). In order to expand the series of allelic mutations in the desmoglein 4 gene underlying LAH in humans, we begin molecular analysis of DSG4 in families from around the world. Here, we describe the study of a family of Pakistani origin with two siblings affected with LAH (Figure 1).This study was supported in part by grants USPHS NIH R01-AR44924 and the March of Dimes Birth Defects Foundation (A. M. C.).Peer reviewe

Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth

Inherited hypertrichoses are rare syndromes characterized by excessive hair growth that does not result from androgen stimulation, and are often associated with additional congenital abnormalities. In this study, we investigated the genetic defect in a case of autosomal recessive congenital generalized hypertrichosis terminalis (CGHT) (OMIM135400) using whole-exome sequencing. We identified a single base pair substitution in the 5′ donor splice site of intron 32 in the ABC lipid transporter gene ABCA5 that leads to aberrant splicing of the transcript and a decrease in protein levels throughout patient hair follicles. The homozygous recessive disruption of ABCA5 leads to reduced lysosome function, which results in an accumulation of autophagosomes, autophagosomal cargos as well as increased endolysosomal cholesterol in CGHT keratinocytes. In an unrelated sporadic case of CGHT, we identified a 1.3 Mb cryptic deletion of chr17q24.2-q24.3 encompassing ABCA5 and found that ABCA5 levels are dramatically reduced throughout patient hair follicles. Collectively, our findings support ABCA5 as a gene underlying the CGHT phenotype and suggest a novel, previously unrecognized role for this gene in regulating hair growth

A Recurrent Intragenic Deletion in the Desmoglein 4 Gene Underlies Localized Autosomal Recessive Hypotrichosis

6 páginas, 2 figuras.A newly defined form of inherited hair loss, named localized autosomal recessive hypotrichosis (LAH, OMIM 607903), was recently described in the literature (Kljuic et al. 2003a; Rafique et al. 2003) and shown to be linked to chromosome 18. We 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. 2003a). LAH is an autosomal recessive form of hypotrichosis affecting the scalp, trunk, and extremities, and 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. 2003a), as well as the lanceolate hair (lah) rat phenotype (Jahoda et al. 2004). In order to expand the series of allelic mutations in the desmoglein 4 gene underlying LAH in humans, we begin molecular analysis of DSG4 in families from around the world. Here, we describe the study of a family of Pakistani origin with two siblings affected with LAH (Figure 1).This study was supported in part by grants USPHS NIH R01-AR44924 and the March of Dimes Birth Defects Foundation (A. M. C.).Peer reviewe

Congenital universal hypertrichosis with deafness and dental anomalies inherited as an X-linked trait

5 páginas, 1 figura, 1 tabla.We report a large Mexican kindred with a variant form of congenital universal hypertrichosis that is inherited in an apparent X-linked recessive manner. In addition to the generalized hypertrichosis, the affected individuals have dental malformations and deafness. Males are more severely affected than females who exhibit only mild hypertrichosis, but not deafness or dental anomalies. Haplotype analysis in this pedigree revealed linkage to a 13-cM region on chromosome Xq24-q27.1 between markers GATA198A10 and DXS8106. Localization of the gene underlying this form of hypertrichosis is the initial step in identifying genes on the X chromosome that are involved in the control of hair growth and development.This work was supported in part by the Skin Disease Research Center in the Department of Dermatology at Columbia University (NIH P30 AR44535) and the Dermatology Foundation.Peer reviewe

Alterations in the hepatic transcriptional landscape after RNAi mediated ApoB silencing in cynomolgus monkeys

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Identification of mutations in the COL7A1 gene in a proband with mild recessive dystrophic epidermolysis bullosa and aortic insufficiency

12 páginas, 2 figuras.We report the clinical and molecular findings in a patient with a mild form of recessive dystrophic epidermolysis bullosa and aortic insufficiency. To our knowledge, this is the first report of association between dystrophic epidermolysis bullosa and abnormalities of the aortic valve. Analysis of the COL7A1 gene has revealed two new mutations, a 20-bp duplication and a splice site mutation.This study was supported by NIH NIAMS R01 AR43602 (A.M.C.).Peer reviewe

A position effect on TRPS1 is associated with Ambras syndrome in humans and the Koala phenotype in mice

Ambras syndrome (AS) is a rare form of congenital hypertrichosis with excessive hair on the shoulders, face and ears. Cytogenetic studies have previously implicated an association with rearrangements of chromosome 8. Here we define an 11.5 Mb candidate interval for AS on chromosome 8q based on cytogenetic breakpoints in three patients. TRPS1, a gene within this interval, was deleted in a patient with an 8q23 chromosomal rearrangement, while its expression was significantly downregulated in another patient with an inversion breakpoint 7.3 Mb downstream of TRPS1. Here, we describe the first potential long-range position effect on the expression of TRPS1. To gain insight into the mechanisms by which Trps1 affects the hair follicle, we performed a detailed analysis of the hair abnormalities in Koa mice, a mouse model of hypertrichosis. We found that the proximal breakpoint of the Koa inversion is located 791 kb upstream of Trps1. Quantitative real-time polymerase chain reaction, in situ hybridization and immunofluorescence analysis revealed that Trps1 expression levels are reduced in Koa mutant mice at the sites of pathology for the phenotype. We determined that the Koa inversion creates a new Sp1 binding site and translocates additional Sp1 binding sites within a highly conserved stretch spanning the proximal breakpoint, providing a potential mechanism for the position effect. Collectively, these results describe a position effect that downregulates TRPS1 expression as the probable cause of hypertrichosis in AS in humans and the Koa phenotype in mice