Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs
Shalini Jadeja1, Ian Smyth, Jolanta E Pitera
1Molecular Medicine Unit, Institute of Child Health, University College London, London WC1N 1EH, UK.
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.
Insights
Fraser syndrome, a genetic disorder causing developmental defects, is linked to mutations in the FRAS1 gene. New research identifies mutations in the related FREM2 gene, uncovering its crucial role in kidney development and epithelial integrity.
Area of Science:
- Genetics
- Developmental Biology
- Molecular Medicine
Background:
- Fraser syndrome is a rare, recessive genetic disorder characterized by cryptophthalmos, syndactyly, and renal defects.
- It is primarily associated with loss-of-function mutations in the extracellular matrix protein FRAS1.
- Fras1 mutant mice exhibit a 'blebbed' phenotype due to intrauterine epithelial fragility.
Purpose of the Study:
- To investigate the genetic basis of the myelencephalic blebs (my) mouse strain, which shares a similar phenotype to Fras1 mutants.
- To determine the role of the FREM2 gene in Fraser syndrome and renal development.
- To identify novel mutations in FREM2 associated with Fraser syndrome.
Main Methods:
- Positional mapping of the 'my' mutation in mice to the Frem2 gene.
- Analysis of a Frem2 gene-trap mutation for allelism with 'my'.
- Examination of Frem2 expression in adult kidneys of 'my' homozygotes.
- Genetic sequencing of FREM2 in individuals with Fraser syndrome.
Main Results:
- The 'my' mutation was mapped to Frem2, and a gene-trap mutation was found to be allelic to 'my'.
- Frem2 expression in adult kidneys correlated with cyst formation in 'my' homozygotes, indicating its role in renal epithelia maintenance.
- Two Fraser syndrome patients were homozygous for the same FREM2 missense mutation, confirming genetic heterogeneity.
Conclusions:
- The FREM2 gene is essential for maintaining the differentiated state of renal epithelia and preventing cyst formation.
- Mutations in FREM2 contribute to Fraser syndrome, highlighting genetic heterogeneity.
- A specific missense mutation in FREM2 suggests the importance of calcium binding in its CALXbeta-cadherin motif for normal function.
