Loss-of-function mutations in FREM2 disrupt eye morphogenesis

Experimental Eye Research
Xiayin ZhangHaotian Lin

Abstract

Cryptophthalmos is a rare congenital disorder characterized by ocular dysplasia with eyelid malformation. Complete cryptophthalmos is characterized by the presence of continuous skin from the forehead over the eyes and onto the cheek, along with complete fusion of the eyelids. In the present study, we characterized the clinical manifestations of three patients with isolated bilateral cryptophthalmos. These patients shared the same c.6499C > T missense mutation in the FRAS1-related extracellular matrix protein 2 (FREM2) gene, while each individual presented an additional nonsense mutation in the same gene (Patient #1, c.2206C > T; Patient #2, c.5309G > A; and Patient #3, c.4063C > T). Then, we used CRISPR/Cas9 to generate mice carrying Frem2R725X/R2156W compound heterozygous mutations, and showed that these mice recapitulated the human isolated cryptophthalmos phenotype. We detected FREM2 expression in the outer plexiform layer of the retina for the first time in the cryptophthalmic eyes, and the levels were comparable to the wild-type mice. Moreover, a set of different expressed genes that may contribute secondarily to the phenotypes were identified by performing RNA sequencing (RNA-seq) of the fetal Frem2 mutant mice. Our find...Continue Reading

Citations

Oct 9, 2019·International Journal of Molecular Sciences·Frédéric Blond, Thierry Léveillard
Jan 26, 2021·Frontiers in Cell and Developmental Biology·Xiayin ZhangHaotian Lin
Aug 20, 2021·Journal of Human Genetics·Piranit Nik KantaputraSissades Tongsima

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