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Gene expression can be regulated at almost every step from gene to protein. Transcription is the step that is most commonly regulated. This involves the binding of proteins to short regulatory sequences on the DNA. This association can either promote or inhibit the transcription of a gene associated with the respective sequence.
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Toward an orofacial gene regulatory network.

Youssef A Kousa1, Brian C Schutte2

  • 1Biochemistry and Molecular Biology Department, Michigan State University, East Lansing, Michigan.

Developmental Dynamics : an Official Publication of the American Association of Anatomists
|September 3, 2015
PubMed
Summary

Interferon regulatory factor 6 (IRF6) variants are linked to orofacial clefting, a common birth defect. This pathway, involving GRHL3 and TFAP2A, is crucial for lip and palate development.

Keywords:
GRHL3IRF6TFAP2AVan der Woude syndromebranchio-oculo-facial syndromecleft lip and palateembryonic developmentmouse modelspopliteal pterygium syndrome

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Area of Science:

  • Genetics
  • Developmental Biology
  • Birth Defects

Background:

  • Orofacial clefting is a common birth defect with substantial morbidity.
  • Interferon regulatory factor 6 (IRF6) gene variants are implicated in both syndromic and isolated forms of orofacial clefting.
  • IRF6 plays a critical role in lip and palate development, with rare variants causing syndromes like Van der Woude syndrome.

Purpose of the Study:

  • To review the genetic pathways involved in orofacial clefting, focusing on the IRF6 pathway.
  • To update current understanding of the genes, pathways, and research directions in orofacial clefting.
  • To highlight ongoing research questions in the field of orofacial clefting.

Main Methods:

  • Literature review integrating findings from animal models and human genetics.
  • Analysis of genetic variants, including rare and common variants, and their association with orofacial clefting.
  • Biochemical studies investigating the functional impact of genetic variants on gene regulation.

Main Results:

  • Rare IRF6 variants cause syndromic orofacial clefting (Van der Woude, popliteal pterygium syndromes).
  • A common IRF6 locus variant (rs642961) increases risk for isolated cleft lip and palate by affecting AP-2alpha binding.
  • IRF6, GRHL3, and TFAP2A (encoding AP-2alpha) are part of a critical developmental pathway for lip and palate formation.

Conclusions:

  • The IRF6-GRHL3-TFAP2A pathway is essential for normal lip and palate development.
  • Both rare and common genetic variants within this pathway contribute to orofacial clefting risk.
  • Further research is needed to fully elucidate the complexities and address current questions in orofacial clefting etiology.