A Review of Orofacial Clefting and Current Genetic Mouse Models

Keteyian, Aram J.; Mishina, Yuji

doi:10.5772/67052

Cited by 1 publication

(1 citation statement)

References 31 publications

(42 reference statements)

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“…Mice have proven to be useful models of human developmental disorders including OFCs. There are hundreds of reported mouse strains, including both gene targeted, spontaneously arisen, and randomly mutagenized (e.g., using N-ethyl-N-nitrosourea) that exhibit OFCs as a component of the phenotype (Keteyian & Mishina, 2017). However, in contrast to humans, the vast majority involve only the secondary palate, with at most just a few dozen displaying CL.…”

Section: Introductionmentioning

confidence: 99%

Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans

Cox

Lidral²,

McCoy

et al. 2019

Human Mutation

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Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.

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Section: Introductionmentioning

confidence: 99%