Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome

Abstract

Background The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well‐organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA‐binding (exon 3, 4) or protein‐binding domains (exon 7–9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico. Methods We used PubMed with the search terms; "Van der Woude syndrome," “Popliteal pterygium syndrome,” "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percentage of deleterious variants. Results Twenty‐one new mutations were identified from nine papers. The majority of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7–9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein‐binding domain (exon 7–9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported nonsense mutations (p.Ser424*and p.Arg250*). Conclusion Mutations in the protein and DNA‐binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.

Novel de novo missense mutation in the interferon regulatory factor 6 gene in an Italian infant with IRF6-related disorder

“…Finally, other similar asparagine missense mutations as asparagine to histidine (p.Asn88His), tyrosine (p.Asn88Tyr), serine (p.Asn88Ser) or isoleucine (p.Asn88Ile) mutations have been reported in VWS1 patients of North European or Latin American origin (PM5) [ 5 , 22 , 23 ], further suggesting that this is an important conserved residue. It is one of the 17 amino acids that are highly predicted to contact the DNA in the 120 amino acids DNA binding domain [ 5 , 24 , 25 ]. Asparagine as a polar amino acid with no charge on the “R” group (side chain) is taking part in the hydrogen bond formation in protein molecules.…”

Uncovering the Pathogenesis of Orofacial Clefts Using Bioinformatics Analysis

“…Case reports of IRF6 mutation from a wide geographical distribution have been reported. [25][26][27][28][29][30] For some cases with OFCs who did not have a mutation in IRF6, mutation in targets of IRF6 have also been studied, such as GRHL3. 31 Researches on function of IRF6 showed mutations in IRF6 may affect different BPs and depend on different molecular mechanisms during embryo development.…”

DNA methylation differences in monozygotic twins with Van der Woude syndrome

“…IRF6 is a transcription factor with a highly conserved helix-turnhelix DNA binding domain and a less conserved SMIR/IAD proteinbinding domain (14). IRF6 is the only member of the IRF gene family involved in craniofacial development and the mutations that cause VWS are non-randomly distributed, with most occurring in the DNA-binding domain (exons 3 and 4) and the protein-binding domain (exons7-9) (15). Since the discovery of IRF6 as the first causal gene for VWS (8), more than 300 mutations have been identified in cases with VWS and PPS (15)(16)(17)(18).…”