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

Shalini Jadeja, Ian Smyth, Jolanta E Pitera, Martin S Taylor, Mieke van Haelst, Elizabeth Bentley, Lesley McGregor, Jason Hopkins, Georges Chalepakis, Nicole Philip, Antonio Perez Aytes, Fiona M Watt, Susan M Darling, Ian Jackson, Adrian S Woolf, Peter J Scambler

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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.

Original languageEnglish
Pages (from-to)520-5
Number of pages6
JournalNature Genetics
Volume37
Issue number5
DOIs
Publication statusPublished - May 2005

Cite this

Jadeja, S., Smyth, I., Pitera, J. E., Taylor, M. S., van Haelst, M., Bentley, E., ... Scambler, P. J. (2005). Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. Nature Genetics, 37(5), 520-5. https://doi.org/10.1038/ng1549