RESUMO
Cranial neural crest (CNC) is a multipotent migratory cell population that gives rise to most of the craniofacial bones. An intricate network mediates CNC formation, epithelial-mesenchymal transition, migration along distinct paths, and differentiation. Errors in these processes lead to craniofacial abnormalities, including cleft lip and palate. Clefts are the most common congenital craniofacial defects. Patients have complications with feeding, speech, hearing, and dental and psychological development. Affected by both genetic predisposition and environmental factors, the complex etiology of clefts remains largely unknown. Here we show that Fas-associated factor-1 (FAF1) is disrupted and that its expression is decreased in a Pierre Robin family with an inherited translocation. Furthermore, the locus is strongly associated with cleft palate and shows an increased relative risk. Expression studies show that faf1 is highly expressed in zebrafish cartilages during embryogenesis. Knockdown of zebrafish faf1 leads to pharyngeal cartilage defects and jaw abnormality as a result of a failure of CNC to differentiate into and express cartilage-specific markers, such as sox9a and col2a1. Administration of faf1 mRNA rescues this phenotype. Our findings therefore identify FAF1 as a regulator of CNC differentiation and show that it predisposes humans to cleft palate and is necessary for lower jaw development in zebrafish.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Fissura Palatina/etiologia , Regulação da Expressão Gênica no Desenvolvimento , Mutação/genética , Crista Neural/metabolismo , Proteínas de Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados , Proteínas Reguladoras de Apoptose , Western Blotting , Cartilagem/metabolismo , Diferenciação Celular , Fissura Palatina/patologia , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Crista Neural/patologia , Linhagem , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
We conducted a genome-wide association study for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 401 affected individuals and 1,323 controls, with replication in an independent sample of 793 NSCL/P triads. We report two new loci associated with NSCL/P at 17q22 (rs227731, combined P = 1.07 x 10(-8), relative risk in homozygotes = 1.84, 95% CI 1.34-2.53) and 10q25.3 (rs7078160, combined P = 1.92 x 10(-8), relative risk in homozygotes = 2.17, 95% CI 1.32-3.56).
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Mapeamento Cromossômico , Fenda Labial/complicações , Fissura Palatina/complicações , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We conducted a genome-wide association study involving 224 cases and 383 controls of Central European origin to identify susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P). A 640-kb region at chromosome 8q24.21 was found to contain multiple markers with highly significant evidence for association with the cleft phenotype, including three markers that reached genome-wide significance. The 640-kb cleft-associated region was saturated with 146 SNP markers and then analyzed in our entire NSCL/P sample of 462 unrelated cases and 954 controls. In the entire sample, the most significant SNP (rs987525) had a P value of 3.34 x 10(-24). The odds ratio was 2.57 (95% CI = 2.02-3.26) for the heterozygous genotype and 6.05 (95% CI = 3.88-9.43) for the homozygous genotype. The calculated population attributable risk for this marker is 0.41, suggesting that this study has identified a major susceptibility locus for NSCL/P.
