RESUMEN
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.
Asunto(s)
Enfermedades Raras/genética , Enfermedades Cutáneas Genéticas/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/genética , Aldehído Oxidorreductasas/genética , Vesícula/genética , Colágeno Tipo VII/genética , Consanguinidad , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Epidermólisis Ampollosa/genética , Epidermólisis Ampollosa Distrófica/genética , Epidermólisis Ampollosa Simple/genética , Exoma , Femenino , Proteínas Filagrina , Flavoproteínas/genética , Homocigoto , Humanos , Mutación INDEL , Eritrodermia Ictiosiforme Congénita/genética , Ictiosis Vulgar/genética , Ictiosis Lamelar/genética , Proteínas de Filamentos Intermediarios/genética , Queratina-14/genética , Errores Innatos del Metabolismo Lipídico/genética , Lipooxigenasa/genética , Masculino , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética , Enfermedades Musculares/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Linaje , Enfermedades Periodontales/genética , Fenotipo , Trastornos por Fotosensibilidad/genética , Porfiria Variegata/genética , Protoporfirinógeno-Oxidasa/genética , Síndrome de Sjögren-Larsson/genética , Factores de Transcripción/genética , Xerodermia Pigmentosa/genéticaRESUMEN
Hereditary hearing impairment (HI) displays extensive genetic heterogeneity. To date, 67 autosomal recessive nonsyndromic hearing impairment (ARNSHI) loci have been mapped, and 24 genes have been identified. This report describes three large consanguineous ARNSHI Pakistani families, all of which display linkage to marker loci located in the genetic interval of DFNB49 locus on chromosome 5q13. Recently, Riazuddin et al. (Am J Hum Genet 2006; 79:1040-1051) reported that variants within the TRIC gene, which encodes tricellulin, are responsible for HI due to DFNB49. TRIC gene sequencing in these three families led to the identification of a novel mutation (IVS4+1G> A) in one family and the discovery of a previously described mutation (IVS4+2T> C) in two families. It is estimated that 1.06% (95% confidence interval 0.02-3.06%) of families with ARNSHI in Pakistan manifest HI due to mutations in the TRIC gene.
Asunto(s)
Genes Recesivos/genética , Pérdida Auditiva/genética , Proteínas de la Membrana/genética , Mutación/genética , Sitios de Empalme de ARN/genética , Mapeo Cromosómico , Cromosomas Humanos Par 2/genética , Consanguinidad , Análisis Mutacional de ADN , Femenino , Ligamiento Genético , Genotipo , Humanos , Escala de Lod , Proteína 2 con Dominio MARVEL , Masculino , Pakistán , Linaje , Reacción en Cadena de la Polimerasa , Uniones EstrechasRESUMEN
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.
Asunto(s)
Anodoncia/genética , Genes Recesivos , Factor de Transcripción MSX1/genética , Mutación Missense , Anomalías Dentarias/genética , Anodoncia/diagnóstico por imagen , Anodoncia/patología , Secuencia de Bases , Consanguinidad , Análisis Mutacional de ADN , Familia , Humanos , Escala de Lod , Datos de Secuencia Molecular , Pakistán , Linaje , Radiografía , Anomalías Dentarias/diagnóstico por imagenRESUMEN
Alopecia with mental retardation syndrome is a rare autosomal recessive disorder characterized clinically by total or partial alopecia and mental retardation. In an effort to understand the molecular bases of this form of alopecia syndrome, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. Genome wide scan mapped the disease locus on chromosome 3q26.33-q27.3. A maximum two-point LOD score of 3.05 (theta = 0.0) was obtained at marker D3S3583. Maximum multipoint LOD score exceeding 5.0, obtained with several markers, supported the linkage. Recombination events observed in affected individuals localized the disease locus between markers D3S1232 and D3S2436, spanning 11.49-cM region on chromosome 3q26.33-q27.3. Sequence analysis of a candidate gene ETS variant gene 5 from DNA samples of two affected individuals of the family revealed no mutation.