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Journal of Lipid Research, Vol. 45, 2361-2367, December 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Phenotypic heterogeneity of sitosterolemia

Jian Wang^*, Tisha Joy^*, David Mymin, Jiri Frohlich and Robert A. Hegele^1,*

^* Robarts Research Institute and University of Western Ontario, London, Ontario, Canada
University of Manitoba, Winnipeg, Manitoba, Canada
St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada

¹ To whom correspondence should be addressed. e-mail: hegele{at}robarts.ca

Sitosterolemia is a rare autosomal recessive disorder of lipoprotein metabolism characterized by xanthomas and increased plasma concentrations of plant sterols, such as sitosterol. Causative mutations occur in either the ABCG5 or ABCG8 gene, each of which encodes a sterol half-transporter expressed in the intestine. We report five Canadian subjects with nonsense mutations in these half-transporters: four related Caucasian subjects were homozygous for the ABCG8 S107X mutation, and one unrelated Japanese-Canadian subject was homozygous for a complex insertion/deletion (I/D) mutation in ABCG5 exon 3. A female subject with each mutation was symptomatic with coronary atherosclerosis: a 5-year-old ABCG8 S107X homozygote and a 75-year-old ABCG5 exon 3 I/D homozygote; these represent the extreme ends of the spectrum of vascular involvement in sitosterolemia. The largest reductions in plasma concentrations of sitosterol and LDL-cholesterol were seen with ezetimibe or bile acid sequestrant treatment, and less dramatic reductions were seen with statin drug treatment.

These findings extend the range of clinical phenotypes in sitosterolemia caused by nonsense mutations in either ABCG5 or ABCG8.

Supplementary key words intestinal absorption • sterols • bile acids • transporters • genomic DNA • mutation • sequence analysis

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