Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs

Abstract

Fraser syndrome is a recessive, multisystem disorder presenting with cryptophthalmos, syndactyly and renal defects and associated with loss-of-function mutations of the extracellular matrix protein FRAS1. Fras1 mutant mice have a blebbed phenotype characterized by intrauterine epithelial fragility generating serous and, later, hemorrhagic blisters. The myelencephalic blebs (my) strain has a similar phenotype. We mapped my to Frem2, a gene related to Fras1 and Frem1, and showed that a Frem2 gene-trap mutation was allelic to my. Expression of Frem2 in adult kidneys correlated with cyst formation in my homozygotes, indicating that the gene is required for maintaining the differentiated state of renal epithelia. Two individuals with Fraser syndrome were homozygous with respect to the same missense mutation of FREM2, confirming genetic heterogeneity. This is the only missense mutation reported in any blebbing mutant or individual with Fraser syndrome, suggesting that calcium binding in the CALXbeta-cadherin motif is important for normal functioning of FREM2.

p63 induces key target genes required for epidermal morphogenesis

“…Among these was the gene encoding Fras1, a keratinocyte-produced extracellular matrix protein which forms a protein complex with its family members Frem1 (Fras1-related ECM protein 1) and Frem2 (Fras1-related ECM protein 2) (37). The absence of any one of these proteins results in a failure of this protein complex to form, causing a severe embryonic blistering phenotype in mice (37)(38)(39)(40). Indeed, real-time RT-PCR analysis confirmed that Fras1 was downregulated in ⌬Np63 i-kd skin (Fig.…”

Crim1KST264/KST264 mice display a disruption of the Crim1 gene resulting in perinatal lethality with defects in multiple organ systems

“…Other genes that, when mutated in the mouse, also result in defects that include syndactyly and eye and kidney malformations include the "blebs" genes in mice (reviewed by Smyth and Scambler, 2005). These encode the proteins, Fras1 (McGregor et al, 2003;Vrontou et al, 2003), Frem1 (Smyth et al, 2004), Frem2 (Jadeja et al, 2005), and Grip1 (Takamiya et al, 2004). Fras1, Frem1, and Frem2 are large, multidomain proteins and possess discrete motifs that are commonly implicated in interactions with extracellular matrix components as well as TGF-␤ superfamily biology .…”

Tissue morphogenesis and vascular stability require the Frem2 protein, product of the mouse myelencephalic blebs gene

“…We mapped my F11 by recombination to a 1.2-Mb region of mouse chromosome 3, which includes the classical mutation myelencephalic blebs (13). The original my mutation causes developmental phenotypes similar to those seen in my F11 , including embryonic blisters and hemorrhages, exencephaly, craniofacial defects, degeneration of the eyes, limb malformations, and renal agenesis (1)(2)(3)6).…”