Identification of the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome gene

Rebecca Leanne Gooding

    Research output: ThesisDoctoral Thesis

    671 Downloads (Pure)

    Abstract

    [Truncated abstract] The Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) syndrome is a novel autosomal recessive developmental disorder, which was identified in (and is so far confined to) a genetically isolated, endogamous group of Gypsies. CCFDN had been mapped to chromosome 18qter, where haplotype homogeneity suggested the presence of a shared founder mutation. The major differential diagnosis is the clinically heterogeneous Marinesco-Sjögren syndrome (MSS). At the beginning of this project, the genetic relationship between the two syndromes was not clear. The project aimed at the identification of the genetic basis of CCFDN and clarifying its relatedness to MSS. Our general approach was positional cloning, exploiting the special characteristics of a founder population. Genes in the critical region were sequenced to identify polymorphisms, which were then used in haplotype analysis and recombination mapping. The characteristics of the Gypsies as an isolate that has undergone a sequence of population bottlenecks with strong founder effects allowed us to use historical recombinations and independent haplotype evolution in different subisolates, thus greatly facilitating the fine mapping. At the final stage of the project, the unusual observation of unaffected parents being homozygous for the "disease" haplotype, led us to develop the novel Not-Quite-Identical-by-Descent (NQIBD) approach, based on the history of the population and epidemiology of the disease. Linkage analysis, haplotype examination and mutation detection were performed for the 18q region and CTDP1, and 5q and the recently identified SIL1 gene (mutated in MSS), in patients and families, clinically diagnosed as Marinesco-Sjögren syndrome. ... A rare mechanism of aberrant splicing resulted in the insertion of intronic sequence in the CTDP1 transcript, predicted to generate a premature termination codon and a truncated protein. Normal transcripts, while still occurring, were reduced to
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2008

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