Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities

Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare rece ssive autosomal inherited disorder, characterised by the presence of tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The defective gene is hypothesised to play an important ro le in regulating dietary sterol absorption and biliary secretion, thus defi ning a molecular mechanism whereby this physiological process is carried ou t. The disease locus was localised previously to chromosome 2p21, in a 15 c M interval between microsatellite markers D2S1788 and D2S1352 (based upon 1 0 families, maximum lodscore 4.49). In this study, we have extended these s tudies to include 30 families assembled from around the world. A maximum mu ltipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity an d haplotype sharing was identified in probands from non-consanguineous marr iages from a number of families, strongly supporting the existence of a fou nder effect among various populations. Additionally, based upon both geneal ogies, as well as genotyping, two Amish/Mennonite families, that were previ ously thought not to be related, appear to indicate a founder effect in thi s population as well. Using both homozygosity mapping, as well as informati ve recombination events, the sitosterolaemia gene is located at a region de fined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM.