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

TitleMutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans.
Publication TypeJournal Article
Year of Publication2019
AuthorsCox, TC, Lidral, AC, McCoy, JC, Liu, H, Cox, LL, Zhu, Y, Anderson, RD, Uribe, LMMoreno, Anand, D, Deng, M, Richter, CT, Nidey, NL, Standley, JM, Blue, EE, Chong, JX, Smith, JD, Kirk, EP, Venselaar, H, Krahn, KN, van Bokhoven, H, Zhou, H, Cornell, RA, Glass, IA, Bamshad, MJ, Nickerson, DA, Murray, JC, Lachke, SA, Thompson, TB, Buckley, MF, Roscioli, T
JournalHum Mutat
Volume40
Issue10
Pagination1813-1825
Date Published2019 10
ISSN1098-1004
Abstract

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.

DOI10.1002/humu.23793
Alternate JournalHum. Mutat.
PubMed ID31215115
PubMed Central IDPMC6764866
Grant List / / Laurel Foundation Endowment for Pediatric Craniofacial Research / International
/ / Cleft Palate Foundation / International
R01 GM127726 / GM / NIGMS NIH HHS / United States
FY98-0718 / / March of Dimes Foundation / International
HG006493 / HG / NHGRI NIH HHS / United States
College of Dentistry Start Up / / Ohio State University / International
6-FY01-616 / / March of Dimes Foundation / International
DE008559 / DE / NIDCR NIH HHS / United States
1U01DE024449-01 / DE / NIDCR NIH HHS / United States
DE024776 / DE / NIDCR NIH HHS / United States
U01 DE020049 / DE / NIDCR NIH HHS / United States
GM114640 / GM / NIGMS NIH HHS / United States
R01 DE014667 / DE / NIDCR NIH HHS / United States
R01 DE023575 / DE / NIDCR NIH HHS / United States
R03 DE024776 / DE / NIDCR NIH HHS / United States
U01 DE020065 / DE / NIDCR NIH HHS / United States
DE014667 / DE / NIDCR NIH HHS / United States
DE023575 / DE / NIDCR NIH HHS / United States
R24 HD000836 / HD / NICHD NIH HHS / United States
Faculty Development Award / / American Association of Orthodontists Foundation / International
U01 DE024449 / DE / NIDCR NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 GM114640 / GM / NIGMS NIH HHS / United States
AU/1/BA51117 / / National Health and Medical Research Council / International
Start Up / / University of Iowa / International
R37 DE008559 / DE / NIDCR NIH HHS / United States
HD000836 / / National Institute of Child Health and Human Development / International