RESUMO
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.
Assuntos
Doenças Raras/genética , Dermatopatias Genéticas/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , Aldeído Oxirredutases/genética , Vesícula/genética , Colágeno Tipo VII/genética , Consanguinidade , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Epidermólise Bolhosa/genética , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Simples/genética , Exoma , Feminino , Proteínas Filagrinas , Flavoproteínas/genética , Homozigoto , Humanos , Mutação INDEL , Eritrodermia Ictiosiforme Congênita/genética , Ictiose Vulgar/genética , Ictiose Lamelar/genética , Proteínas de Filamentos Intermediários/genética , Queratina-14/genética , Erros Inatos do Metabolismo Lipídico/genética , Lipoxigenase/genética , Masculino , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Doenças Musculares/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Linhagem , Doenças Periodontais/genética , Fenótipo , Transtornos de Fotossensibilidade/genética , Porfiria Variegada/genética , Protoporfirinogênio Oxidase/genética , Síndrome de Sjogren-Larsson/genética , Fatores de Transcrição/genética , Xeroderma Pigmentoso/genéticaRESUMO
Tooth agenesis constitutes the most common anomaly of dental development in humans. In the majority of familial cases of hypodontia alone or in association with other anomalies, the mode of inheritance is autosomal dominant. In the present study, we have identified two distantly related consanguineous Pakistani kindreds with an autosomal recessive form of oligodontia with associated dental anomalies. Locus in this case has been mapped on chromosome 4p16.1-p16.3. The maximum two-point LOD score of 2.85 (theta=0.0) was obtained at markers D4S2925 and D4S2285. A maximum multipoint LOD score exceeding 4 was obtained at the same markers. Recombination events observed in affected individuals localized the disease locus between markers D4S412 and D4S2935, spanning a 9.24-cM region on chromosome 4p16.1-p16.3. Sequence analysis of candidate gene MSX1 revealed a novel recessive missense mutation resulting in substitution of alanine to threonine amino acid (p. A219T), located in the MSX1 homeodomain, which is important for DNA binding and protein-protein interaction. The mutation, p. A219T, is the first recessive mutation identified in MSX1.