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Development of a microsatellite-based approach to co-segregation analysis of familial hypercholesterolaemic kindreds

Haddad, L; Day, LB; Attwood, J; Povey, S; Humphries, SE; Day, INM; (1997) Development of a microsatellite-based approach to co-segregation analysis of familial hypercholesterolaemic kindreds. ANN HUM GENET , 61 497 - 506.

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Abstract

Co-segregation studies based on a selection of intragenic restriction fragment length polymorphisms of the low density lipoprotein receptor (LDLR) gene hare been used extensively both for research and diagnostic studies of familial hypercholesterolaemia (FH) families, because direct mutation screening remains complex. Here we describe the development and application of a more efficient approach to co-segregation studies based on highly informative dinucleotide and tetranucleotide repeats flanking the LDLR gene. A series of microsatellites (D19S391, D19S394, D19S221 and D19S179) were selected for study on the basis of linkage analysis in the CEPH families using intragenic polymorphisms for a TA repeat (exon 18) in the LDLR gene, and earlier data for a Pvu II polymorphism (intron 15). A physical map of the region of chromosome 19 also contributed to this selection. One marker in particular, D19S394, sited 150 kilobases telomeric to the gene, was extremely useful, displaying 90% heterozygosity, robust TCR of tetranucleotide repeats without stutter bands, and no recombination with the LDLR gene (theta = 0, LOD 68). Use of this marker in the families of twenty-three FH probands from Hampshire demonstrated co-segregation of the hyperlipidaemia phenotype with the LDLR gene region, except in one family with defective apolipoprotein B-100, and a family turning out to display familial combined hyperlipidaemia. This approach should facilitate the search for any families where FH does not co-segregate with the LDLR gene, and will enhance the repertoire of molecular diagnostic tools available for FH.

Type:Article
Title:Development of a microsatellite-based approach to co-segregation analysis of familial hypercholesterolaemic kindreds
Keywords:LDL-RECEPTOR GENE, DENSITY-LIPOPROTEIN RECEPTOR, CONFORMATIONAL POLYMORPHISM METHOD, DEFECTIVE APOLIPOPROTEIN-B-100, UNITED-KINGDOM, HUMAN GENOME, DNA, MUTATION, LINKAGE, MARKERS
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of)
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science

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