Journal article
Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans
Human mutation, Vol.40(10), pp.1813-1825
10/01/2019
DOI: 10.1002/humu.23793
PMCID: PMC6764866
PMID: 31215115
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.
Details
- Title: Subtitle
- Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans
- Creators
- Timothy C. Cox - University of WashingtonAndrew C. Lidral - Lidral Orthodontics, Rockford, Michigan.Jason C. McCoy - University of CincinnatiHuan Liu - University of IowaLiza L. Cox - University of WashingtonYing Zhu - Prince of Wales HospitalRyan D. Anderson - University of MissouriLina M. Moreno Uribe - University of IowaDeepti Anand - University of DelawareMei Deng - University of WashingtonChika T. Richter - University of IowaNichole L. Nidey - University of IowaJennifer M. Standley - University of IowaElizabeth E. Blue - University of WashingtonJessica X. Chong - University of WashingtonJoshua D. Smith - University of WashingtonEdwin P. Kirk - Sydney Children's HospitalHanka Venselaar - Radboud University Medical CenterKaty N. Krahn - University of Virginia Medical CenterHans van Bokhoven - Radboud University NijmegenHuiqing Zhou - Radboud Institute for Molecular Life SciencesRobert A. Cornell - Univ Iowa, Dept Anat & Cell Biol & Anat, Iowa City, IA USAIan A. Glass - University of WashingtonMichael J. Bamshad - University of WashingtonDeborah A. Nickerson - University of WashingtonJeffrey C. Murray - University of IowaSalil A. Lachke - University of DelawareThomas B. Thompson - University of CincinnatiMichael F. Buckley - Prince of Wales HospitalTony Roscioli - Prince of Wales Hospital
- Resource Type
- Journal article
- Publication Details
- Human mutation, Vol.40(10), pp.1813-1825
- DOI
- 10.1002/humu.23793
- PMID
- 31215115
- PMCID
- PMC6764866
- NLM abbreviation
- Hum Mutat
- ISSN
- 1059-7794
- eISSN
- 1098-1004
- Publisher
- Wiley
- Number of pages
- 13
- Grant note
- R01DE023575; R56DE023575; U01DE024449; R03DE024776 / NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Dental & Craniofacial Research (NIDCR) Australian NHMRC Project; National Health and Medical Research Council (NHMRC) of Australia UM1HG006493 / NATIONAL HUMAN GENOME RESEARCH INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) R24HD000836 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) R01GM127726 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 10/01/2019
- Academic Unit
- Orthodontics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Addiction Medicine; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984367644902771
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