RESUMO
Discriminating between inherited and non-inherited sporadic hearing loss is challenging. Here, we attempted to delineate genetic inheritance in simplex cases of severe-to-profound congenital hearing loss in Korean children. Variations in SLC26A4 and GJB2 in 28 children with bilateral severe-to-profound non-syndromic hearing loss (NSHL) without familial history were analyzed using Sanger sequencing. Genetic analysis of individuals without mutations in SLC26A4 and GJB2 was performed by whole exome sequencing (WES). Bi-allelic mutations in SLC26A4 and GJB2 were identified in 12 and 3 subjects, respectively. Of the 13 individuals without mutations in SLC26A4 and GJB2, 2 and 1 carried compound heterozygous mutations in MYO15A and CDH23, respectively. Thus, 64.3% (18/28) of individuals with NSHL were determined to be genetically predisposed. Individuals with sporadic severe-to-profound NSHL were found to mostly exhibit an autosomal recessive inheritance pattern. Novel causative candidate genes for NSHL were identified by analysis of WES data of 10 families without mutations in known causative genes. Bi-allelic mutations predisposing to NSHL were identified in 64.3% of subjects with sporadic severe-to-profound NSHL. Given that several causative genes for NSHL are still unidentified, genetic inheritance of sporadic congenital hearing loss could be more common than that indicated by our results.
Assuntos
Predisposição Genética para Doença , Perda Auditiva/congênito , Perda Auditiva/genética , Alelos , Audiometria , Criança , Pré-Escolar , Implante Coclear , Conexina 26/genética , Família , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Proteínas de Membrana Transportadoras/genética , Mutação/genética , Linhagem , Fenótipo , Transportadores de Sulfato , Sequenciamento do ExomaRESUMO
Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole-exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat-shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle's loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or VACTERL association with CAKUT.
Assuntos
Canal Anal/anormalidades , Análise Mutacional de DNA , Esôfago/anormalidades , Exossomos , Testes Genéticos , Proteínas de Choque Térmico HSP90 , Cardiopatias Congênitas/genética , Rim/anormalidades , Deformidades Congênitas dos Membros/genética , Mutação , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Refluxo Vesicoureteral/genética , Fatores Etários , Animais , Análise Mutacional de DNA/métodos , Europa (Continente) , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença , Testes Genéticos/métodos , Idade Gestacional , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Cardiopatias Congênitas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Rim/embriologia , Rim/metabolismo , Deformidades Congênitas dos Membros/diagnóstico , Masculino , Camundongos , Reação em Cadeia da Polimerase Multiplex , Linhagem , Valor Preditivo dos Testes , Fatores de Risco , Estados Unidos , Anormalidades Urogenitais , Refluxo Vesicoureteral/diagnósticoRESUMO
Cholesterol is known to modulate the physical properties of cell membranes, but its direct involvement in cellular signaling has not been thoroughly investigated. Here we show that cholesterol specifically binds many PDZ domains found in scaffold proteins, including the N-terminal PDZ domain of NHERF1/EBP50. This modular domain has a cholesterol-binding site topologically distinct from its canonical protein-binding site and serves as a dual-specificity domain that bridges the membrane and juxta-membrane signaling complexes. Disruption of the cholesterol-binding activity of NHERF1 largely abrogates its dynamic co-localization with and activation of cystic fibrosis transmembrane conductance regulator, one of its binding partners in the plasma membrane of mammalian cells. At least seven more PDZ domains from other scaffold proteins also bind cholesterol and have cholesterol-binding sites, suggesting that cholesterol modulates cell signaling through direct interactions with these scaffold proteins. This mechanism may provide an alternative explanation for the formation of signaling platforms in cholesterol-rich membrane domains.
