Keratin 71 Mutations: From Water Dogs to Woolly Hair

The study of rare genetic disorders of the hair follicle has resulted in the identification of many causative genes, leading to the potential for the development of novel therapeutic approaches for both inherited and acquired hair disorders. In this issue, Fujimoto et al. identify a missense mutation within the keratin 71 (KRT71) gene as the cause for autosomal dominant woolly hair/hypotrichosis in a Japanese family. This represents the first human mutation in KRT71 to be linked to a hair disorder, establishing this gene as an important determinant of mammalian hair texture. Moreover, this finding provides new insight into the relationship between similar phenotypes resulting from mutations in distinct regulatory pathways and underscores the role of the inner root sheath in human hair growth

Niche Crosstalk: Intercellular Signals at the Hair Follicle

A recent series of papers, including Festa et al. (2011) in this issue, has revealed unexpected interdependent relationships among cell populations residing in and around the hair follicle. These interactions between different lineages of stem cells are crucial for hair follicle growth and cycling and point to a complex crosstalk in stem cell niches

Genetic Basis of Dominantly Inherited Transient Bullous Dermolysis of the Newborn: A Splice Site Mutation in the Type VII Collagen Gene

Transient bullous dermolysis of the newborn (TBDN) is a blistering disease evident at birth or shortly thereafter, but the blistering tendency decreases with advancing age. The tissue separation in TBDN is below the lamina densa, and electron microscopy has revealed abnormalities in anchoring fibrils. Immunofluorescence staining demonstrates intracellular accumulation of type VII collagen. In this study, we report a G-to-C transversion mutation in the last nucleotide of intron 35 of the type VII collagen gene (COL7A1) in a family with autosomal dominant TBDN in three generations. This nucleotide substitution abolishes the obligatory consensus 3'-acceptor splice site, predicting in-frame skipping of exon 36. Thus, TBDN in this family is caused by a mutation in COL7A1, and is therefore allelic with other variants of dominant dystrophic epidermolysis bullosa

Genetic Basis of Dominantly Inherited Transient Bullous Dermolysis of the Newborn: A Splice Site Mutation in the Type VII Collagen Gene

Transient bullous dermolysis of the newborn (TBDN) is a blistering disease evident at birth or shortly thereafter, but the blistering tendency decreases with advancing age. The tissue separation in TBDN is below the lamina densa, and electron microscopy has revealed abnormalities in anchoring fibrils. Immunofluorescence staining demonstrates intracellular accumulation of type VII collagen. In this study, we report a G-to-C transversion mutation in the last nucleotide of intron 35 of the type VII collagen gene (COL7A1) in a family with autosomal dominant TBDN in three generations. This nucleotide substitution abolishes the obligatory consensus 3'-acceptor splice site, predicting in-frame skipping of exon 36. Thus, TBDN in this family is caused by a mutation in COL7A1, and is therefore allelic with other variants of dominant dystrophic epidermolysis bullosa

Elevated expression of type VII collagen in the skin of patients with systemic sclerosis. Regulation by transforming growth factor-beta.

A hallmark of systemic sclerosis (SSc) is the development of tissue fibrosis. Excessive production of several connective tissue components normally present in the dermis, including type I, III, V, and VI collagens as well as fibronectin and proteoglycans, is a consistent finding in the skin of SSc patients. Type VII collagen is a major constituent of anchoring fibrils, present in the skin at the dermal-epidermal basement membrane zone. TGF-beta has been shown to upregulate the expression of the type VII collagen gene. In this study, we assessed the expression of type VII collagen and TGF-beta in the skin of patients with SSc. Indirect immunofluorescence showed an abundance of type VII collagen in the patients\u27 skin, including the dermis. Ultrastructural analysis of SSc skin revealed an abundance of fibrillar material, possibly representing type VII collagen. The increased expression of type VII collagen epitopes was accompanied by the elevated expression of immunodetectable TGF-beta 1 and TGF-beta 2. Dermal fibroblasts cultured from the affected individuals showed a statistically significant (P \u3c 0.02) increase in the expression of type VII collagen at the mRNA level, as detected by reverse transcription-PCR with a mutated cDNA as an internal standard, and increased deposition of the protein as assessed by indirect immunofluorescence. Thus, type VII collagen is abundantly present in SSc patients\u27 dermis, a location not characteristic of its normal distribution, and its aberrant expression may relate to the presence of TGF-beta in the same topographic distribution. The presence of type VII collagen in the dermis may contribute to the tightly bound and indurated appearance of the affected skin in SSc patients

Introduction to Innovations in the Immunology and Clinical Science of Alopecia Areata

Alopecia areata is an autoimmune skin disease resulting in the loss of hair on the scalp and elsewhere on the body. The disease most often occurs in childhood and affects males and females of all ages. The National Alopecia Areata Foundation conducts research summits every 2 years to review progress and create new directions in its funded and promoted research. The Foundation brings together scientists from all disciplines to get a broad and varied perspective. These summits are part of the Foundation’s main strategic initiative, the Alopecia Areata Treatment Development Program to accelerate progress toward a viable alopecia areata treatment

Trps1 and Its Target Gene Sox9 Regulate Epithelial Proliferation in the Developing Hair Follicle and Are Associated with Hypertrichosis

Hereditary hypertrichoses are a group of hair overgrowth syndromes that are extremely rare in humans. We have previously demonstrated that a position effect on TRPS1 is associated with hypertrichosis in humans and mice. To gain insight into the functional role of Trps1, we analyzed the late morphogenesis vibrissae phenotype of Trps1Δgt mutant mice, which is characterized by follicle degeneration after peg downgrowth has been initiated. We found that Trps1 directly represses expression of the hair follicle stem cell regulator Sox9 to control proliferation of the follicle epithelium. Furthermore, we identified a copy number variation upstream of SOX9 in a family with hypertrichosis that significantly decreases expression of the gene in the hair follicle, providing new insights into the long-range regulation of SOX9. Our findings uncover a novel transcriptional hierarchy that regulates epithelial proliferation in the developing hair follicle and contributes to the pathology of hypertrichosis

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