The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.

TitleThe role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.
Publication TypeJournal Article
Year of Publication2018
AuthorsJordan, VK, Beck, TF, Hernandez-Garcia, A, Kundert, PN, Kim, B-J, Jhangiani, SN, Gambin, T, Starkovich, M, Punetha, J, Paine, IS, Posey, JE, Li, AH, Muzny, DM, Hsu, C-W, Lashua, AJ, Sun, X, Fernandes, CJ, Dickinson, ME, Lally, KP, Gibbs, RA, Boerwinkle, E, Lupski, JR, Scott, DA
JournalHum Mol Genet
Date Published2018 Jun 15
KeywordsAnimals, Child, Child, Preschool, Epithelium, Extracellular Matrix Proteins, Female, Hernias, Diaphragmatic, Congenital, Humans, Infant, Infant, Newborn, Male, Mice, Mice, Knockout, Mutation, Pregnancy, Receptors, Interleukin

Congenital diaphragmatic hernia (CDH) has been reported twice in individuals with a clinical diagnosis of Fraser syndrome, a genetic disorder that can be caused by recessive mutations affecting FREM2 and FRAS1. In the extracellular matrix, FREM2 and FRAS1 form a self-stabilizing complex with FREM1, a protein whose deficiency causes sac CDH in humans and mice. By sequencing FREM2 and FRAS1 in a CDH cohort, and searching online databases, we identified five individuals who carried recessive or double heterozygous, putatively deleterious variants in these genes which may represent susceptibility alleles. Three of these alleles were significantly enriched in our CDH cohort compared with ethnically matched controls. We subsequently demonstrated that 8% of Frem2ne/ne and 1% of Fras1Q1263*/Q1263* mice develop the same type of anterior sac CDH seen in FREM1-deficient mice. We went on to show that development of sac hernias in FREM1-deficient mice is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. Based on these data, we conclude that deficiency of FREM2, and possibly FRAS1, are associated with an increased risk of developing CDH and that loss of the FREM1/FREM2/FRAS1 complex, or its function, leads to anterior sac CDH development through its effects on mesothelial fold progression.

Alternate JournalHum Mol Genet
PubMed ID29618029
PubMed Central IDPMC5985720
Grant ListR01 HD064667 / HD / NICHD NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
UM1 HG006348 / HG / NHGRI NIH HHS / United States
R25 GM056929 / GM / NIGMS NIH HHS / United States
U54 HG006348 / HG / NHGRI NIH HHS / United States
/ / Wellcome Trust / United Kingdom
T32 GM008307 / GM / NIGMS NIH HHS / United States

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