Novel and de novo mutations of the IRF6 gene detected in patients with Van der Woude or popliteal pterygium syndrome

Abstract

The interferon regulatory factor 6 gene (IRF6) has been identified as the major Van der Woude (VWS) syndrome and popliteal pterygium (PPS) syndrome gene with mutations in the majority of the kindreds. We have studied altogether 17 kindreds from Sweden, Finland, Norway, Thailand and Singapore, and report here 10 mutations, six of them previously unseen. In two kindreds, we could document de novo mutations, both of them changing a codon for a glutamine residue to a stop. No mutation could be detected in the four VWS kindreds from Finland, suggesting a founder effect for a mutation in an atypical noncoding position. Our findings demonstrate that several distinct mutations occur in the Swedish population, and confirm the general notion of a broad spectrum of IRF6 mutations underlying the VWS/PPS phenotypes.

Disease-associated mutations in IRF6 and RIPK4 dysregulate their signalling functions

“…Additional nonsense mutations (e.g. p.Ser424X) that may also abrogate RIPK4-mediated IRF6 activation similarly have been reported in VWS [15][16][17]. While the functional significance of these mutations has not been established, our findings suggest that in addition to promoting IRF6 degradation, they may also prevent the activation of IRF6 by RIPK4.…”

“…However, a p.Arg412X nonsense mutation predicted to cause the truncation of IRF6 at Arg412 was the most common mutation identified in two geographically separate cohorts of N300 families with VWS [15]. The same mutation was also identified in other studies [5,[16][17][18][19][20][21], suggesting that it represents a mutational hotspot in VWS. A small number of RIPK4 mutations in BPS have been identified [6,7].…”

“…Importantly, their mutation causes the congenital developmental syndromes, VWS and PPS, and the related but more severe BPS, respectively [5][6][7]. A p.Arg412X nonsense mutation immediately proximal to regulatory phosphorylation sites in IRF6 is prevalent in VWS, but less common in PPS [5,[15][16][17][18][19][20][21]. A nonsense mutation in the intermediate domain of RIPK4 (p.Ser376X) was recently identified in BPS [7].…”

<i>IRF6</i> Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign

“…3 B). All three mutations identified in families A, B and C have been reported in other VWS families [Kondo et al, 2002;Wang et al, 2003Wang et al, , 2005Ghassibe et al, 2004;Peyrard-Janvid et al, 2005;de Lima et al, 2009].…”

Hydrocephalus and moderate mental retardation in a boy with Van der Woude phenotype and IRF6 gene mutation

“…The molecular basis of most of these conditions is not yet known. VWS and PPS display marked phenotypic variability and are caused by different mutations in IRF6 gene (Kondo et al, 2002;Ghassibé et al, 2004;Item et al, 2005;Peyrard-Janvid et al, 2005).…”