Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes

Abstract

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.

A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

“…10,11 In addition, IRF6 (interferon regulatory factor 6) and RIPK4 have been implicated in PPS. 8,9,12 We found that similar to IRF6 mutants, 10,11,13 RIPK4 − / − mice 1 have a defective skin barrier function and cleft palate, and RIPK4 − / − keratinocytes fail to differentiate in vitro. In Xenopus, we show that IRF6 controls RIPK4 expression and that RIPK4 can rescue developmental defects imposed by IRF6 dysfunction, thereby identifying a novel genetic interaction between IRF6 and RIPK4.…”

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

“…In the other report, a mutation, Glu92X, in interferon regulatory factor 6 (IRF6) was identified in a MZ twin having Van der Woude syndrome characterized by the cleft lip and palate with lip pits, whose healthy co-twin did not have this disease. 21 This mutation was not found in healthy co-twins and their parents. They reported this finding as one of the evidences to prove the causative role of IRF6 in Van der Woude syndrome.…”

Infants with Bochdalek diaphragmatic hernia: Sibling precurrence and monozygotic twin discordance in a hospital‐based malformation surveillance program

“…Post-zygotic de novo mutations, as well as epigenetic differences are mechanisms proven to underlie MZ twin discordance [Kondo et al, 2002;Weksberg et al, 2002]. The latter mechanism has been documented in twins with Beckwith Wiedemann syndrome (BWS).…”

“…The discovery of mutations in the interferon regulatory factor 6 gene (IRF6) as the cause of lip pit or van der Woude syndrome could be a model for identifying multifactorial genetic changes contributing to CDH. Specifically, mutations in both the IRF6 protein binding domain and the DNA binding domain produce van der Woude syndrome; recent studies demonstrate that a common variant in IRF6 increases the risk for isolated cleft lip and palate [Kondo et al, 2002;Kayano et al, 2003;Zucchero et al, 2004;Scapoli et al, 2005]. Thus, possible mutations or clusters of polymorphisms in FOG2, WT1 and, other as yet unidentified major development genes or their downstream targets, could contribute to multifactorial causation of CDH.…”