title: Phytosterolemia on the island of Kosrae: founder effect for a novel ABCG8 mutation results in high carrier rate and increased plasma plant sterol levels.
abstract: Screening of 932 adults on the Pacific island of Kosrae for plasma plant sterol levels disclosed three subjects, two of them asymptomatic, with phytosterolemia. Sequencing the ATP binding cassette subfamily G member 8 (ABCG8) gene revealed a novel exon 2 mutation that causes a change in codon 24 from glutamine to histidine and a frame shift followed by a premature stop codon, precluding the formation of a functional ABCG8 protein. Genotyping of 1,090 Kosraens revealed 150 as carriers, a 13.8% carrier rate. DNA sequencing of 67 carriers revealed the same mutation as in the probands. In carriers, plasma campesterol and sitosterol levels were 55% and 30% higher, respectively, than in noncarriers. Moreover, compared with noncarriers, carriers showed 21% lower plasma levels of lathosterol, a surrogate marker for cholesterol biosynthesis. There was no difference between the groups in plasma total cholesterol, triglycerides, apolipoprotein B, or apolipoprotein A-I levels. In summary, on the island of Kosrae, a strong founder effect of a mutant ABCG8 allele results in a large number of carriers with increased plasma plant sterol levels and decreased lathosterol levels. The latter finding suggests that heterozygosity for a mutated ABCG8 allele results in a modest increase in dietary cholesterol absorption and a decrease in cholesterol biosynthesis.
authors.affiliation: Laboratories of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY, USA. sehayee@rockefeller.edu
authors.forename: Ephraim
authors.initials: E
authors.lastname: Sehayek
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Yu
authors.forename: Klaus
authors.initials: K
authors.lastname: von Bergmann
authors.forename: Dieter
authors.initials: D
authors.lastname: Lutjohann
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Duncan
authors.forename: Laura
authors.initials: L
authors.lastname: Garcia-Naveda
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Salit
authors.forename: Maude L
authors.initials: ML
authors.lastname: Blundell
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Friedman
authors.forename: Jan L
authors.initials: JL
authors.lastname: Breslow
mesh_terms: D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004032:Diet; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood* / Q000235:genetics*; D008074:Lipoproteins / Q000235:genetics*; D008297:Male; D008849:Micronesia; D008875:Middle Aged; D009154:Mutation; D010802:Phylogeny; D010840:Phytosterols / Q000097:blood*
chemical_list: C416946:ABCG8 protein, human; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins; D010840:Phytosterols