RESUMEN
Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-alpha and -beta after viral infection, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32-q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits, and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies. Phenotypic overlap and linkage data suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.
Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Proteínas de Unión al ADN/genética , Genitales/anomalías , Anomalías Cutáneas/genética , Factores de Transcripción/genética , Animales , Sitios de Unión/genética , Sitios de Unión/fisiología , Northern Blotting , ADN/metabolismo , Enfermedades en Gemelos/genética , Femenino , Humanos , Hibridación in Situ , Factores Reguladores del Interferón , Masculino , Ratones , Mutación Missense , Linaje , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Relación Estructura-Actividad , Síndrome , Gemelos Monocigóticos/genéticaRESUMEN
We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.
Asunto(s)
Autoinmunidad/genética , Neoplasias de la Mama/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , Espondilitis Anquilosante/genética , Tiroiditis Autoinmune/genética , Aminopeptidasas/genética , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Mapeo Cromosómico , Genética de Población , Genotipo , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento , Antígenos de Histocompatibilidad Menor , Esclerosis Múltiple/epidemiología , América del Norte/epidemiología , Reacción en Cadena de la Polimerasa , Receptores Inmunológicos/genética , Receptores de Interleucina/genética , Espondilitis Anquilosante/epidemiología , Tiroiditis Autoinmune/epidemiologíaRESUMEN
Development of the lip and palate involves a complex series of events that are frequently disturbed resulting in the congenital anomalies cleft lip and cleft palate. Van der Woude syndrome (VWS) is an autosomal dominant disorder that is characterised by cleft lip, cleft palate, lower lip pits, and hypodontia. VWS arises as the result of mutations in the gene encoding interferon regulatory factor 6 (IRF6). To provide insights into the role of IRF6 during embryogenesis, we have analysed the expression of this molecule during mouse and chick facial development. Irf6 was expressed in the ectoderm covering the facial processes during their fusion to form the upper lip and primary palate in both mouse and chick. However, while Irf6 was expressed in the medial edge epithelia of the developing secondary palate of the mouse, which fuses as in man, Irf6 was not expressed in the medial edge epithelia of the naturally cleft chick secondary palate. Similarly, Irf6 was found to be down-regulated in the medial edge epithelia of transforming growth factor beta3-null mice, which also exhibit cleft palate. Together, these results support a role for IRF6 during the fusion events that occur during development of the lip and palate.