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

University of Crete, Retimo, Crete, Greece
Nature Genetics (Impact Factor: 29.35). 06/2005; 37(5):520-5. DOI: 10.1038/ng1549
Source: PubMed


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.

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    • "Taken together autosomal dominant inheritance of AMS with a high proportion of de novo mutations appears more likely than the previously suggested autosomal recessive transmission [Rohena et al., 2011]. Mutations in three genes, FRAS1, FREM2, and GRIP1, are known to cause FS [McGregor et al., 2003; Jadeja et al., 2005; Vogel et al., 2012]. The products of these genes act together with a fourth component, FREM1, and form a mutually stabilized, extracellular matrix protein complex that is expressed in basement membranes during embryonic development and contributes to embryonic epithelial-mesenchymal integrity [Smyth and Scambler, 2005; Kiyozumi et al., 2006]. "
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    ABSTRACT: Ablepharon macrostomia syndrome (AMS; OMIM 200110) is an extremely rare congenital malformation syndrome. It overlaps clinically with Fraser syndrome (FS; OMIM 219000), which is known to be caused by mutations in either FRAS1, FREM2, or GRIP1, encoding components of a protein complex that plays a role in epidermal-dermal interactions during morphogenetic processes. We explored the hypothesis that AMS might be either allelic to FS or caused by mutations in other genes encoding known FRAS1 interacting partners. No mutation in either of these genes was found in a cohort of 11 patients with AMS from 10 unrelated families. These findings demonstrate that AMS is genetically distinct from FS. It is proposed that it constitutes a separate entity within the group of FRAS-FREM complex disorders. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Dec 2013 · American Journal of Medical Genetics Part A
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    • "Each of the blebs mutants have strongly overlapping phenotypes. Indeed, the Fras1 and Frem2 mutants have indistinguishable phenotypes and Fras1/Frem2 double homozygous mice exhibit a spectrum of birth defects similar to those observed in single homozygotes, suggesting strongly overlapping functions [5]. Similarly, even though heb is the phenotypic outlier of the blebs group in that the phenotype is notably milder than the other blebs mice, the range of phenotypes observed in heb are completely encompassed by those exhibited by the other three blebs mutants [8]. "
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    ABSTRACT: Fras1 is an extracellular matrix associated protein with essential roles in adhesion of epithelia and mesenchyme during early embryonic development. The adhesive function of Fras1 is achieved through interaction with a group of related proteins, Frem 1-3, and a cytoplasmic adaptor protein Grip1. Mutation of each of these proteins results in characteristic epithelial blistering and have therefore become known as "blebs" proteins. Human Fraser syndrome presents with a similar phenotype and the blebs mice have been instrumental in identification of the genetic basis of Fraser syndrome. We have identified a new ENU-induced blebs allele resulting from a novel missense mutation in Fras1. The resulting mouse strain, blood filled blisters (bfb), presents with a classic blebs phenotype but does not exhibit embryonic lethality typical of other blebs mutants and in addition, we report novel palate and sternal defects. Analysis of the bfb phenotype confirms the presence of epithelial-mesenchymal adhesion defects but also supports the emerging role of blebs proteins in regulating signalling during organogenesis. The bfb strain provides new opportunities to investigate the role of Fras1 in development.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "Mutations in FRAS1 (607830.0001) and FREM2 (608945.0001) genes have been previously found to be responsible for about half of cases [McGregor et al., 2003; Jadeja et al., 2005; Shafeghati et al., 2008; van Haelst et al., 2008]. Recently, mutations in GRIP1 gene have also been identified to cause Fraser syndrome in humans [Vogel et al., 2012]. "
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    ABSTRACT: Fraser syndrome is a rare autosomal recessive disorder characterized by cryptophthalmos, cutaneous syndactyly, laryngeal, and urogenital malformations. We present a population-based epidemiological study using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network of birth defect registries. Between January 1990 and December 2008, we identified 26 cases of Fraser syndrome in the monitored population of 12,886,464 births (minimal estimated prevalence of 0.20 per 100,000 or 1:495,633 births). Most cases (18/26; 69%) were registered in the western part of Europe, where the mean prevalence is 1 in 230,695 births, compared to the prevalence 1 in 1,091,175 for the rest of Europe (P = 0.0003). Consanguinity was present in 7/26 (27%) families. Ten (38%) cases were liveborn, 14 (54%) pregnancies were terminated following prenatal detection of a serious anomaly, and 2 (8%) were stillborn. Eye anomalies were found in 20/24 (83%), syndactyly in 14/24 (58%), and laryngeal anomalies in 5/24 (21%) patients. Ambiguous genitalia were observed in 3/24 (13%) cases. Bilateral renal agenesis was present in 12/24 (50%) and unilateral in 4/24 (17%) cases. The frequency of anorectal anomalies was particularly high (42%). Most cases of Fraser syndrome (85%) are suspected prenatally, often due to the presence of the association of renal agenesis and cryptophthalmos. In the European population, a high proportion (82%) of pregnancies is terminated, thus reducing the live birth prevalence to a third of the total prevalence rate. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · May 2013 · American Journal of Medical Genetics Part A
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