Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome

Abstract

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell–cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

ZebraShare: a new venue for rapid dissemination of zebrafish mutant data

“…Consistent with the zebrafish findings, the p120catenin protein encoded by ctnnd1 has several known roles in early development, and murine loss-of-function models are embryonic lethal when homozygous (Hernández-Martínez, Ramkumar & Anderson, 2019). The mouse Ctnnd1 neural crest knockout line shows cleft palate when heterozygous, and consistent defects are seen in humans heterozygous for CTNND1 truncation alleles (Alharatani et al, 2020). Ctnnd1 is involved in cadherin stabilization, WNT signaling during gastrulation and epithelial-to-mesenchymal transitions, and suppression of the RhoA-ROCK-myosin pathway (Pieters et al, 2016;Yu et al, 2016;Hernández-Martínez, Ramkumar & Anderson, 2019).…”

“…New discoveries may stimulate new interest in submitted lines. While there was no clear disease connection when the ctnnd1 homozygous lethal phenotypes were submitted to ZebraShare, subsequent analysis of the heterozygote reveals a more specific cellular disassociation at the embryo's dorsal edge, which could potentially be related to neural crest defects recently reported in humans with CTNND1 gene variants (Alharatani et al, 2020). Finally, ZebraShare may also provide information about alleles which reproduce phenotypes found already in publication and offers a way to quickly share phenotypes that verify or contradict the literature.…”

Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios

“…Additional studies will be necessary to determine the proportion of OFCs accounted for by these genes and any differences between DNMs and inherited variants described in multiplex families, including detailed phenotyping of individuals and families carrying these variants. 71 Historically, CL/P and CP have been considered distinct disorders, so we performed multiple analyses in CL/P and CP separately to determine if this is supported by DNMs. 2 Both CL/P and CP had a significant excess of protein-altering DNMs, although the excess of DNMs in the CL/P-affected trios was more apparent.…”

Identification of key pathways and genes in polycystic ovary syndrome via integrated bioinformatics analysis and prediction of small therapeutic molecules

“…The GO and pathway enrichment analysis was of great importance for interpreting the molecular mechanisms of the key cellular activities in PCOS. RPS5 [ 37 ], RBM3 [ 38 ], BAK1 [ 39 ], NDUFC2 [ 40 ], NDUFS4 [ 41 ], NDUFS5 [ 42 ], UQCRFS1 [ 43 ], COX6B1 [ 44 ], NDUFA13 [ 45 ], PRMT1 [ 46 ], RDX (radixin) [ 47 ], EPHB4 [ 48 ], SYNE2 [ 49 ], DNAH5 [ 50 ], NEDD4L [ 51 ], PDE4B [ 52 ] and CTNND1 [ 53 ] plays a critical role in the process of cardiovascular disease, but these genes might be linked with development of PCOS. Ostergaard et al [ 54 ], Zi et al [ 55 ], Kunej et al [ 56 ], Van der Schueren et al [ 57 ], Jin et al [ 58 ], Emdad et al [ 59 ], Liu et al [ 60 ], Scherag et al [ 61 ], Shi and Long [ 62 ], Sharma et al [ 63 ], Parente et al [ 64 ], Saint-Laurent et al [ 65 ] and Lee [ 66 ] demonstrated that over expression of COA3, PHB (prohibitin), UQCRC1, COX4I1, IFI27, MTDH (metadherin), S100A16, SDCCAG8, GLI2, NTN1, NLGN2, FGFR3 and PTPRN2 could cause obesity, but these genes might be involved in progression of PCOS.…”