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The FRAS1-related extracellular matrix 1 ( FREM1 ) gene encodes an extracellular matrix protein that plays a critical role in the development of multiple organ systems. In humans, recessive mutations in  FREM1  cause eye defects, congenital diaphragmatic hernia, renal anomalies and anorectal malformations including anteriorly placed anus. A similar constellation of findings–microphthalmia, cryptophthalmos, congenital diaphragmatic hernia, renal agenesis and rectal prolapse–have been described in FREM1-deficient mice. In this paper, we identify a homozygous  Frem1  missense mutation (c.1687A>T, p.Ile563Phe) in an N-ethyl-N-nitrosourea (ENU)-derived mouse strain,  crf11 , with microphthalmia, cryptophthalmos, renal agenesis and rectal prolapse. This mutation affects a highly conserved residue in FREM1’s third CSPG domain. The p.Ile563Phe change is predicted to be deleterious and to cause decreased FREM1 protein stability. The  crf11  allele also fails to complement the previously described  eyes2  allele of  Frem1  (p.Lys826*) providing further evidence that the  crf11  phenotype is due to changes affecting  Frem1  function. We then use mice bearing the  crf11  and  eyes2  alleles to identify lung lobulation defects and decreased anogenital distance in males as novel phenotypes associated with FREM1 deficiency in mice. Due to phenotypic overlaps between FREM1 - deficient mice and mice that are deficient for the retinoic acid-responsive transcription factor GATA4 and the extracellular matrix protein SLIT3, we also perform experiments to look for  in vivo  genetic interactions between the genes that encode these proteins. These experiments reveal that  Frem1  interacts genetically with  Gata4  in the development of lung lobulation defects and with  Slit3  in the development of renal agenesis. These results demonstrate that FREM1-deficient mice faithfully recapitulate many of the phenotypes seen in individuals with FREM1 deficiency and that variations in GATA4 and SLIT3 expression modulate some FREM1-related phenotypes in mice.

Novel Frem1-Related Mouse Phenotypes and Evidence of Genetic Interactions with Gata4 and Slit3