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1.
PLoS One ; 7(9): e45441, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23029012

RESUMEN

Previous evidence from tooth agenesis studies suggested IRF6 and TGFA interact. Since tooth agenesis is commonly found in individuals with cleft lip/palate (CL/P), we used four large cohorts to evaluate if IRF6 and TGFA interaction contributes to CL/P. Markers within and flanking IRF6 and TGFA genes were tested using Taqman or SYBR green chemistries for case-control analyses in 1,000 Brazilian individuals. We looked for evidence of gene-gene interaction between IRF6 and TGFA by testing if markers associated with CL/P were overtransmitted together in the case-control Brazilian dataset and in the additional family datasets. Genotypes for an additional 142 case-parent trios from South America drawn from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), 154 cases from Latvia, and 8,717 individuals from several cohorts were available for replication of tests for interaction. Tgfa and Irf6 expression at critical stages during palatogenesis was analyzed in wild type and Irf6 knockout mice. Markers in and near IRF6 and TGFA were associated with CL/P in the Brazilian cohort (p<10(-6)). IRF6 was also associated with cleft palate (CP) with impaction of permanent teeth (p<10(-6)). Statistical evidence of interaction between IRF6 and TGFA was found in all data sets (p = 0.013 for Brazilians; p = 0.046 for ECLAMC; p = 10(-6) for Latvians, and p = 0.003 for the 8,717 individuals). Tgfa was not expressed in the palatal tissues of Irf6 knockout mice. IRF6 and TGFA contribute to subsets of CL/P with specific dental anomalies. Moreover, this potential IRF6-TGFA interaction may account for as much as 1% to 10% of CL/P cases. The Irf6-knockout model further supports the evidence of IRF6-TGFA interaction found in humans.


Asunto(s)
Labio Leporino/metabolismo , Fisura del Paladar/metabolismo , Factores Reguladores del Interferón/metabolismo , Factor de Crecimiento Transformador alfa/metabolismo , Animales , Brasil , Labio Leporino/genética , Fisura del Paladar/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Factores Reguladores del Interferón/genética , Desequilibrio de Ligamiento/genética , Ratones , Polimorfismo de Nucleótido Simple/genética , Unión Proteica , Factor de Crecimiento Transformador alfa/genética , Población Blanca
2.
Genet Med ; 11(4): 241-7, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19282774

RESUMEN

PURPOSE: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome. METHODS: We performed direct sequence analysis of interferon regulatory factor 6 exons on samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome. RESULTS: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further, the missense mutations associated with popliteal pterygium syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. CONCLUSION: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. On the other hand, the distribution of popliteal pterygium syndrome-associated mutations suggests a different, though not mutually exclusive, effect on interferon regulatory factor 6 function.


Asunto(s)
Anomalías Múltiples/genética , Labio Leporino/patología , Fisura del Paladar/patología , Factores Reguladores del Interferón/genética , Mutación , Anomalías Múltiples/patología , Secuencia de Aminoácidos , Sitios de Unión/genética , Análisis Mutacional de ADN , Exones , Salud de la Familia , Femenino , Frecuencia de los Genes , Humanos , Deformidades Congénitas de las Extremidades Inferiores/patología , Masculino , Datos de Secuencia Molecular , Síndrome
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