Toward an orofacial gene regulatory network.
Orofacial clefting is a common birth defect with significant morbidity. A panoply of candidate genes have been discovered through synergy of animal models and human genetics. Among these, variants in interferon regulatory factor 6 (IRF6) cause syndromic orofacial clefting and contribute risk toward isolated cleft lip and palate (1/700 live births). Rare variants in IRF6 can lead to Van der Woude syndrome (1/35,000 live births) and popliteal pterygium syndrome (1/300,000 live births). Furthermore, IRF6 regulates GRHL3 and rare variants in this downstream target can also lead to Van der Woude syndrome. In addition, a common variant (rs642961) in the IRF6 locus is found in 30% of the world's population and contributes risk for isolated orofacial clefting. Biochemical studies revealed that rs642961 abrogates one of four AP-2alpha binding sites. Like IRF6 and GRHL3, rare variants in TFAP2A can also lead to syndromic orofacial clefting with lip pits (branchio-oculo-facial syndrome). The literature suggests that AP-2alpha, IRF6 and GRHL3 are part of a pathway that is essential for lip and palate development. In addition to updating the pathways, players and pursuits, this review will highlight some of the current questions in the study of orofacial clefting.
Biochemistry and Molecular Biology Department, Michigan State University, East Lansing, Michigan.
Youssef A
YA
Kousa
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan.
Brian C
BC
Schutte
D000015:Abnormalities, Multiple / Q000453:epidemiology* / Q000235:genetics; D002971:Cleft Lip / Q000453:epidemiology* / Q000235:genetics; D002972:Cleft Palate / Q000453:epidemiology* / Q000235:genetics; D003560:Cysts / Q000453:epidemiology* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008046:Lip / Q000002:abnormalities*; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C473143:GRHL3 protein, human; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D014157:Transcription Factors
GRHL3; IRF6; TFAP2A; Van der Woude syndrome; branchio-oculo-facial syndrome; cleft lip and palate; embryonic development; mouse models; popliteal pterygium syndrome