title: Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities.
abstract: Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare recessive 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 role in regulating dietary sterol absorption and biliary secretion, thus defining a molecular mechanism whereby this physiological process is carried out. The disease locus was localised previously to chromosome 2p21, in a 15 cM interval between microsatellite markers D2S1788 and D2S1352 (based upon 10 families, maximum lodscore 4.49). In this study, we have extended these studies to include 30 families assembled from around the world. A maximum multipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity and haplotype sharing was identified in probands from non-consanguineous marriages from a number of families, strongly supporting the existence of a founder effect among various populations. Additionally, based upon both genealogies, as well as genotyping, two Amish/Mennonite families, that were previously thought not to be related, appear to indicate a founder effect in this population as well. Using both homozygosity mapping, as well as informative recombination events, the sitosterolaemia gene is located at a region defined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM.
authors.affiliation: Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, Charleston, SC 29403, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Lee
authors.forename: D
authors.initials: D
authors.lastname: Gordon
authors.forename: J
authors.initials: J
authors.lastname: Ott
authors.forename: K
authors.initials: K
authors.lastname: Lu
authors.forename: L
authors.initials: L
authors.lastname: Ose
authors.forename: T
authors.initials: T
authors.lastname: Miettinen
authors.forename: H
authors.initials: H
authors.lastname: Gylling
authors.forename: A F
authors.initials: AF
authors.lastname: Stalenhoef
authors.forename: A
authors.initials: A
authors.lastname: Pandya
authors.forename: H
authors.initials: H
authors.lastname: Hidaka
authors.forename: B
authors.initials: B
authors.lastname: Brewer
authors.forename: H
authors.initials: H
authors.lastname: Kojima
authors.forename: N
authors.initials: N
authors.lastname: Sakuma
authors.forename: R
authors.initials: R
authors.lastname: Pegoraro
authors.forename: G
authors.initials: G
authors.lastname: Salen
authors.forename: S B
authors.initials: SB
authors.lastname: Patel
mesh_terms: D001161:Arteriosclerosis / Q000235:genetics; D002791:Cholesterol, Dietary / Q000378:metabolism; D002874:Chromosome Mapping / Q000379:methods; D002889:Chromosomes, Human, Pair 2; D004032:Diet; D018703:Founder Effect; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007408:Intestinal Absorption / Q000235:genetics; D015810:Linkage Disequilibrium; D008659:Metabolic Diseases / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D008957:Models, Genetic; D010375:Pedigree; D010802:Phylogeny; D012855:Sitosterols / Q000378:metabolism*
chemical_list: D002791:Cholesterol, Dietary; D012855:Sitosterols