Titre :

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

Auteur(s) :

Petit, Florence [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Longoni, Mauro [Auteur]
Massachusetts General Hospital [Boston]
Wells, Julie [Auteur]
The Jackson Laboratory [Bar Harbor] [JAX]
Maser, Richard S. [Auteur]
The Jackson Laboratory [Bar Harbor] [JAX]
Bogenschutz, Eric L. [Auteur]
The Jackson Laboratory [Bar Harbor] [JAX]
Dysart, Matthew J. [Auteur]
Massachusetts General Hospital [Boston]
Contreras, Hannah T. M. [Auteur]
Massachusetts General Hospital [Boston]
Frenois, Frederic [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Pober, Barbara R. [Auteur]
Massachusetts General Hospital [Boston]
Clark, Robin D. [Auteur]
Loma Linda University
Giampietro, Philip F. [Auteur]
University of Illinois [Chicago] [UIC]
Ropers, Hilger H. [Auteur]
Max Planck Institute for Molecular Genetics [MPIMG]
Hu, Hao [Auteur]
Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement (LASIRE) - UMR 8516
Loscertales, Maria [Auteur]
Massachusetts General Hospital [Boston]
Wagner, Richard [Auteur]
Massachusetts General Hospital [Boston]
Ai, Xingbin [Auteur]
Massachusetts General Hospital [Boston]
Brand, Harrison [Auteur]
Harvard Medical School [Boston] [HMS]
Jourdain, Anne-Sophie [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Delrue, Marie-Ange [Auteur]
Centre Hospitalier Universitaire de Bordeaux [CHU Bordeaux]
Gilbert-Dussardier, Brigitte [Auteur]
Université de Poitiers = University of Poitiers [UP]
Devisme, Louise [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Keren, Boris [Auteur]
CHU Pitié-Salpêtrière [AP-HP]
McCulley, David J. [Auteur]
University of California [UC]
Qiao, Lu [Auteur]
Columbia University [New York]
Hernan, Rebecca [Auteur]
Columbia University Medical Center [CUMC]
Wynn, Julia [Auteur]
Columbia University [New York]
Scott, Tiana M. [Auteur]
Brigham Young University [BYU]
Calame, Daniel G. [Auteur]
Baylor College of Medicine [BCM]
Coban-Akdemir, Zeynep [Auteur]
Baylor College of Medicine [BCM]
Hernandez, Patricia [Auteur]
Baylor College of Medicine [BCM]
Hernandez-Garcia, Andres [Auteur]
Baylor College of Medicine [BCM]
Yonath, Hagith [Auteur]
Tel Aviv University [TAU]
Lupski, James R. [Auteur]
Baylor College of Medicine [BCM]
Shen, Yufeng [Auteur]
Columbia University [New York]
Chung, Wendy K. [Auteur]
Boston Children's Hospital
Scott, Daryl A. [Auteur]
Baylor College of Medecine
Bult, Carol J. [Auteur]
The Jackson Laboratory [Bar Harbor] [JAX]
Donahoe, Patricia K. [Auteur]
Massachusetts General Hospital [Boston]
High, Frances A. [Auteur]
Massachusetts General Hospital [Boston]

Titre de la revue :

Am. J. Hum. Genet.

Nom court de la revue :

Am. J. Hum. Genet.

Numéro :

110

Pagination :

-

Date de publication :

2023-11-26

ISSN :

0002-9297

Mot(s)-clé(s) en anglais :

PLS3
plastin
X-linked
abdominal hernia
actin-binding protein
congenital diaphragmatic hernia
fimbrin
omphalocele
umbilical hernia

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

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 ...
Lire la suite >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.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

Université de Lille
CHU Lille

Collections :

• Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364

Date de dépôt :

2023-12-15T05:23:46Z
2024-06-26T08:45:11Z