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

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.

RETRACTED: Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling

“…The gene encoding GDF11 has been mapped to a region of chromosome 12q13.2, which encodes a novel protein of 407 aa with a signal sequence for secretion, an RXXR proteolytic processing site, and a carboxyl terminal region containing a highly conserved pattern of cysteine residues. 42 , 43 , 44 , 45 Improving GDF11 expression has been shown to reduce ischemic stroke injury in mice. 46 , 47 Our results showed a negative regulation between miR-125b-5p and GDF11, indicating a potential neurotoxic role of miR-125b-5p.…”

Characterization of tolloid-mediated cleavage of the GDF8 procomplex

“…While most strategies rely on inhibiting GDF8 post-translationally, recent studies have implied that non-functional variants of GDF11 can have a dominant negative effect on WT GDF11 (65). Because TGFβ ligands are covalent dimers, this is likely due to the non-functional copy combining with the WT version, forming a less functional procomplex.…”

Allele-specific gene regulation by KDM6A

“…KDM6A targets common to both reciprocal crosses include genes such as Gdf11 and Sox11 previously implicated in development of the roof of the mouth and hard palate, malformations of which are often seen in Kabuki syndrome due to mutations in KDM6A (Bogershausen et al, 2016;Silva-Andrade et al, 2019;Yap et al, 2020). GDF11 mutations in human lead to orofacial abnormalities, while SOX11 has a role in human palatogenesis (Cox et al, 2019;Khan et al, 2018;Suzuki et al, 2018). Our findings of additional dysregulated genes may help identify other gene targets implicated in congenital defects seen in Kabuki syndrome (Bogershausen et al, 2016;Lintas and Persico, 2018).…”