TY - JOUR
T1 - Dominant mutations in GRHL3 cause Van der Woude syndrome and disrupt oral periderm development
AU - Peyrard-Janvid, Myriam
AU - Leslie, Elizabeth J.
AU - Kousa, Youssef A.
AU - Smith, Tiffany L.
AU - Dunnwald, Martine
AU - Magnusson, Måns
AU - Lentz, Brian A.
AU - Unneberg, Per
AU - Fransson, Ingegerd
AU - Koillinen, Hannele K.
AU - Rautio, Jorma
AU - Pegelow, Marie
AU - Karsten, Agneta
AU - Basel-Vanagaite, Lina
AU - Gordon, William
AU - Andersen, Bogi
AU - Svensson, Thomas
AU - Murray, Jeffrey C.
AU - Cornell, Robert A.
AU - Kere, Juha
AU - Schutte, Brian C.
N1 - Funding Information:
We greatly appreciate the many individuals affected with VWS, their family members, and clinicians for participating in this study. We would like to thank Arianna L. Smith and Mager Scientific for technical assistance; Nicole Patel for the artistic renderings of murine embryos at E13.5 and E15.5; Päivi Lahermo for providing the Finnish controls and Pat Venta for critiques. Financial support for this research was provided by the Swedish Research Council 521-2007-3133 (M.P.-J.) and 2009-5091 (J.K.), by National Institutes of Health grants DE021071 (R.A.C.), DE13513 (B.C.S.), F31DE022696 (Y.A.K.), DE08559 (J.C.M.), GM008629 (E.J.L.), AR061586 (M.D.), and AR44882 (B.A.), and by the Sigrid Jusélius Foundation (J.K.).
PY - 2014/1/2
Y1 - 2014/1/2
N2 - Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6 +/-;Grhl3+/-) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.
AB - Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6 +/-;Grhl3+/-) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.
UR - http://www.scopus.com/inward/record.url?scp=84891832380&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2013.11.009
DO - 10.1016/j.ajhg.2013.11.009
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AN - SCOPUS:84891832380
SN - 0002-9297
VL - 94
SP - 23
EP - 32
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -