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

TitlePLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects.
Publication TypeJournal Article
Year of Publication2023
AuthorsPetit, F, Longoni, M, Wells, J, Maser, RS, Bogenschutz, EL, Dysart, MJ, Contreras, HTM, Frénois, F, Pober, BR, Clark, RD, Giampietro, PF, Ropers, HH, Hu, H, Loscertales, M, Wagner, R, Ai, X, Brand, H, Jourdain, A-S, Delrue, M-A, Gilbert-Dussardier, B, Devisme, L, Keren, B, McCulley, DJ, Qiao, L, Hernan, R, Wynn, J, Scott, TM, Calame, DG, Coban-Akdemir, Z, Hernandez, P, Hernandez-Garcia, A, Yonath, H, Lupski, JR, Shen, Y, Chung, WK, Scott, DA, Bult, CJ, Donahoe, PK, High, FA
JournalAm J Hum Genet
Date Published2023 Oct 05
KeywordsActins, Adult, Animals, Hernias, Diaphragmatic, Congenital, Humans, Male, Mice, Mutation, Missense, Osteoporosis

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.

Alternate JournalAm J Hum Genet
PubMed ID37751738
PubMed Central IDPMC10577083
Grant ListHHSN268201100037C / HL / NHLBI NIH HHS / United States
R01 HD098458 / HD / NICHD NIH HHS / United States
R01 HD057036 / HD / NICHD NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
P01 HD068250 / HD / NICHD NIH HHS / United States

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