Van der Woude syndrome (VWS, OMIM #119300) is the most common cleft syndrome accounting for 2% of all cleft cases with a prevalance of 1/35'000 to 1/100'000 newborns. Many VWS individuals (30-79%) present with very characteristic depression (pits) near the center of the lower lip in combination with CLP or cleft palate only. The condition is caused by gene mutations and is inherited in an autosomal dominant way.
Initially, the VWS locus was mapped to human chromosome 1q32-q41 and the gene encoding for the transcription factor Interferon Regulatory Factor 6 (IRF6) was found to be mutated in around 72% of VWS cases (Kondo et al., 2002). Later, dominant-negative mutations within the transcription factor grainyhead like transcription factor 3 (GRHL3), a direct target gene of IRF6, have been identified in VWS-affected families not having pathogenic mutations in IRF6 (Peyrard-Janvid et al., 2014). More recently, a third VWS-associated gene has been discovered: a rare missense mutation within NME1, encoding for an IRF6-interacting proteins, was found to cause VWS in individuals not having IRF6 and GRHL3 mutations (Parada-Sanchez et al., 2017).
Most literature is available on the function of IRF6 in VWS: Keratinocytes isolated from skin biopsies from the hip region of VWS individuals (harboring IRF6 mutations) exhibit an increased proliferation rate (Hixon et al., 2016) and VWS patients experience more wound healing complications following repair of their clefts (Jones et al., 2010) compared to non-syndromic CLP keratinocytes and patients, respectively. Up to now, more than 200 mutations within IRF6 have been found associated with either VWS, popliteal pterygium syndrome (PPS, OMIM #119500), which can mimic the allelic disorder VWS in mild cases, or with non-syndromic CLP. However, the underlying mechanistic link between gene mutation and phenotype remains elusive for most of them.
Using a combination of genetics, molecular and cellular biology we aim to establish genotype-phenotype correlations in VWS-patients, which should help to understand gene function in health and disease.
In collaboration with: PD. A. Schaller, Division of Human Genetics, Children's Hospital Bern, Switzerland http://www.kinderkliniken.insel.ch/de/kinderkliniken/kinderheilkunde/kiheil-humangenetik/ and Dr.med. I. Schnyder, Pediatric Surgery Department, Children's Hospital Bern, Switzerland http://www.kinderkliniken.insel.ch/de/kinderkliniken/kikli-chirurgie/kikli-spezsprechstd21/kikli-info-lkg1/