McGregor, Lesley Karen; (2003) The molecular genetics of Fraser syndrome. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Fraser syndrome is a rare congenital autosomal recessive syndrome. The major features are cryptophthalmos, syndactyly, laryngeal stenosis and renal agenesis. The aim of this project was to identify the gene(s) causing Fraser syndrome, initially by linkage mapping of the gene using the technique of homozygosity mapping and then using a positional cloning approach to identify suitable candidate genes that could be screened for disease causing mutations. Linkage was determined to chromosome 4q21 in a 1.5cM area homologous with that containing the blebbed mouse gene, previously postulated to be a model for Fraser syndrome. Physical mapping and bioinformatics provided a BAC contig across the linked region, containing two annotated genes (ANX3, PRDM8) and a novel serine threonine kinase. These genes were sequenced and no mutations were found. Four novel genes upstream of ANX3 were identified containing domains involved in signal transduction and formation of the extracellular matrix. Sequencing commenced. A collaboration then provided the cDNA sequence used in a targeted gene knockout causing an identical phenotype to the blebbed mouse. The human homolog of this gene mapped to chromosome 4q21 and encompassed three of the four novel transcripts. The complete human cDNA was determined and one frameshift and four nonsense mutations were subsequently identified within this 75 exon gene named FRAS1. A second locus for Fraser syndrome was subsequently located on human chromosome 13q13.3 utilising sequence homology to FRAS1 and mapping data available in the mouse for the myelencephalic gene and a gene provisionally named FRAS2, has been identified at this locus. It is suggested that a defective FRAS1 protein causes an early to mid-gestational developmental defect due to a defective extracellular matrix which may be accompanied by a disruption of signalling. Mechanical or pressure effects from blisters caused by the separation of the dermis and basement membrane and subsequent fluid retention may influence the severity of the malformations seen on this background.

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