Research: PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects

Am J Hum Genet

. 2023 Sep 20;S0002-9297(23)00315-4.

 doi: 10.1016/j.ajhg.2023.09.002. Online ahead of print.

PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects

Florence Petit 1Mauro Longoni 2Julie Wells 3Richard S Maser 3Eric L Bogenschutz 3Matthew J Dysart 4Hannah T M Contreras 4Frederic Frénois 5Barbara R Pober 6Robin D Clark 7Philip F Giampietro 8Hilger H Ropers 9Hao Hu 9Maria Loscertales 2Richard Wagner 10Xingbin Ai 6Harrison Brand 11Anne-Sophie Jourdain 5Marie-Ange Delrue 12Brigitte Gilbert-Dussardier 13Louise Devisme 14Boris Keren 15David J McCulley 16Lu Qiao 17Rebecca Hernan 17Julia Wynn 17Tiana M Scott 18Daniel G Calame 19Zeynep Coban-Akdemir 20Patricia Hernandez 21Andres Hernandez-Garcia 22Hagith Yonath 23James R Lupski 24Yufeng Shen 25Wendy K Chung 26Daryl A Scott 27Carol J Bult 3Patricia K Donahoe 2Frances A High 28

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Congenital 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 an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), 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 adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.

Keywords: PLS3, plastin; X-linked; abdominal hernia; actin-binding protein; congenital diaphragmatic hernia; fimbrin; omphalocele; umbilical hernia.

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