ABSTRACT
BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study. METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families. RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes. CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.
Subject(s)
Rare Diseases/genetics , Skin Diseases, Genetic/genetics , 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics , Aldehyde Oxidoreductases/genetics , Blister/genetics , Collagen Type VII/genetics , Consanguinity , DNA Mutational Analysis , DNA-Binding Proteins/genetics , Endonucleases/genetics , Epidermolysis Bullosa/genetics , Epidermolysis Bullosa Dystrophica/genetics , Epidermolysis Bullosa Simplex/genetics , Exome , Female , Filaggrin Proteins , Flavoproteins/genetics , Homozygote , Humans , INDEL Mutation , Ichthyosiform Erythroderma, Congenital/genetics , Ichthyosis Vulgaris/genetics , Ichthyosis, Lamellar/genetics , Intermediate Filament Proteins/genetics , Keratin-14/genetics , Lipid Metabolism, Inborn Errors/genetics , Lipoxygenase/genetics , Male , Membrane Proteins/genetics , Mitochondrial Proteins/genetics , Muscular Diseases/genetics , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Pedigree , Periodontal Diseases/genetics , Phenotype , Photosensitivity Disorders/genetics , Porphyria, Variegate/genetics , Protoporphyrinogen Oxidase/genetics , Sjogren-Larsson Syndrome/genetics , Transcription Factors/genetics , Xeroderma Pigmentosum/geneticsABSTRACT
Cyclic AMP (cAMP) production, which is important for mechanotransduction within the inner ear, is catalyzed by adenylate cyclases (AC). However, knowledge of the role of ACs in hearing is limited. Previously, a novel autosomal recessive non-syndromic hearing impairment locus DFNB44 was mapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan. Through whole-exome sequencing of DNA samples from hearing-impaired family members, a nonsense mutation c.3112C>T (p.Arg1038*) within adenylate cyclase 1 (ADCY1) was identified. This stop-gained mutation segregated with hearing impairment within the family and was not identified in ethnically matched controls or within variant databases. This mutation is predicted to cause the loss of 82 amino acids from the carboxyl tail, including highly conserved residues within the catalytic domain, plus a calmodulin-stimulation defect, both of which are expected to decrease enzymatic efficiency. Individuals who are homozygous for this mutation had symmetric, mild-to-moderate mixed hearing impairment. Zebrafish adcy1b morphants had no FM1-43 dye uptake and lacked startle response, indicating hair cell dysfunction and gross hearing impairment. In the mouse, Adcy1 expression was observed throughout inner ear development and maturation. ADCY1 was localized to the cytoplasm of supporting cells and hair cells of the cochlea and vestibule and also to cochlear hair cell nuclei and stereocilia. Ex vivo studies in COS-7 cells suggest that the carboxyl tail of ADCY1 is essential for localization to actin-based microvilli. These results demonstrate that ADCY1 has an evolutionarily conserved role in hearing and that cAMP signaling is important to hair cell function within the inner ear.
