Author:
Petit Florence,Longoni Mauro,Wells Julie,Maser Richard,Dysart Matthew J.,Contreras Hannah T.M.,Frénois Frederic,Bogenschutz Eric,Pober Barbara R.,Clark Robin D.,Giampietro Philip F.,Ropers Hilger H.,Hu Hao,Loscertales Maria,Ai Xingbin,Brand Harrison,Jourdain Anne-Sophie,Delrue Marie-Ange,Gilbert-Dussardier Brigitte,Devisme Louise,Keren Boris,McCulley David J.,Qiao Lu,Hernan Rebecca,Wynn Julia,Scott Tiana M.,Calame Daniel G.,Coban-Akdemir Zeynep,Hernandez Patricia,Hernandez-Garcia Andres,Yonath Hagith,Lupski James R.,Shen Yufeng,Chung Wendy K.,Scott Daryl A.,Bult Carol J.,Donahoe Patricia K.,High Frances A.
Abstract
ABSTRACTCongenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with a novel X-linked condition characterized by diaphragm defects, variable anterior body wall anomalies, and/or facial dysmorphism. Using linkage analysis and whole exome or whole genome sequencing, we identified novel missense variants in the actin binding domains of plastin 3 (PLS3), a gene encoding an actin bundling protein, that co-segregate with disease in all families. Loss-of-function variants in PLS3 have been described previously in association with X-linked osteoporosis. To address these seemingly disparate clinical phenotypes, we performed in silico protein modeling and cellular overexpression experiments, which suggest that the affected residues in individuals with CDH are important for actin binding and result in disorganization of the actin cytoskeleton and a reduction in normal actin stress fiber formation. A mouse knock-in model of a variant identified in one of the families, p.W499C, shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal wall defects. Both the mouse model and one surviving adult patient with a PLS3 variant were observed to have increased, rather than decreased, bone mineral density. Together, these clinical and functional data in human and mouse reveal that specific missense variants affecting the actin binding domains of PLS3 may have a gain-of-function effect and cause a new Mendelian disorder.
Publisher
Cold Spring Harbor Laboratory
Reference50 articles.
1. Longoni, M. , Pober, B.R. , and High, F.A. (1993). Congenital Diaphragmatic Hernia Overview. In GeneReviews((R)), M.P. Adam , H.H. Ardinger , R.A. Pagon , S.E. Wallace , L.J.H. Bean , G. Mirzaa , and A. Amemiya , eds.
2. The influence of genetics in congenital diaphragmatic hernia
3. Systematic analysis of copy number variation associated with congenital diaphragmatic hernia
4. De novo copy number variants are associated with congenital diaphragmatic hernia
5. Increased burden ofde novopredicted deleterious variants in complex congenital diaphragmatic hernia
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献