Am J Hum Genet

. 2023 Sep 20;S0002-9297(23)00315-4.

 doi: 10.1016/j.ajhg.2023.09.002. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/37751738/

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

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

Affiliations expand

• PMID: 37751738
• DOI: 10.1016/j.ajhg.2023.09.002

Abstract

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.

Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.