High-resolution physical and transcript map of human chromosome 2p21 containing the sitosterolaemia locus

Lu, Kangmo; Lee, Mi-Hye; Carpten, John D.; Sekhon, Mandeep; Patel, Shailendra B.

doi:10.1038/sj.ejhg.5200627

Cited by 13 publications

(16 citation statements)

References 42 publications

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“…Mutational analyses showed that both of these genes could be mutated in sitosterolemia. Patel and colleagues, pursuing a more classical approach, also simultaneously identified ABCG5 and ABCG8 as mutant in sitosterolemia (23,24,27,28). Surprisingly, affected individuals are completely mutant for either ABCG5 or ABCG8, but to date, no affected proband has been identified who is mutant for both genes (28).…”

Section: Genetics Of Sitosterolemiamentioning

confidence: 99%

“…A concerted effort by Patel, Salen, Grundy and colleagues to assemble and analyze a very large cohort of pedigrees led to the confirmation of an autosomal recessive pattern of inheritance, and they mapped the sitosterolemia locus to human chromosome 2p21 (39). Further progress led the Patel team to fine map this locus to a region less than 2 cM (23,27). In 2000, two groups simultaneously identified the gene defect(s) in sitosterolemia (4,23,24,28).…”

Section: Genetics Of Sitosterolemiamentioning

confidence: 99%

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Sitosterolemia

Salen

and

Batta

2002

Cardiovascular Drug Reviews

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Sitosterolemia was first described 28 years ago in two sisters. They had tendon xanthomas, normal plasma cholesterol levels, and elevated plant sterol levels. The high plant sterol levels were shown to be due to the increased absorption and delayed removal of plant sterols from the body. The increased absorption of plant sterols does not affect cholesterol absorption in these patients. However, cholesterol biosynthesis pathway is downregulated and turnover rates are reduced. Bile acid binding resins and ileal bypass surgery are effective treatments for sitosterolemic patients, whereas statins are ineffective. Sitosterolemia is inherited as a recessive trait. Recent studies have shown that mutations in ABCG5 and ABCG8 genes contribute to sitosterolemia. Most likely, ABCG5 and ABCG8 proteins function as obligate heterodimers and play a role in the absorption of plant sterol or control their rate of absorption.

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Section: Genetics Of Sitosterolemiamentioning

confidence: 99%

Section: Genetics Of Sitosterolemiamentioning

confidence: 99%

Sitosterolemia

Salen

and

Batta

2002

Cardiovascular Drug Reviews

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“…We performed linkage analyses of 10 well-characterized pedigrees and mapped the sitosterolemia locus, STSL, to human chromosome 2p21, between microsatellite markers D2S1788 and D2S1352 3,12,14 . The disease locus interval was narrowed further and a physical map of this region constructed that allowed for the positional cloning of the sitosterolemia 'gene' 14 .…”

Section: Genetics Of Sitosterolemiamentioning

confidence: 99%

Plant sterols and stanols: Their role in health and disease

Patel

2008

Journal of Clinical Lipidology

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Mammalian physiological processes, and likely any organism with a biliary tree, can distinguish between dietary cholesterol and non-cholesterols, retaining very little of the non-cholesterol in their bodies. Historically, the distinction between plant sterols and cholesterol has been known about for a century or more. That plants sterols were not 'absorbed' has been investigated for almost half a century. Indeed, the oral of plant sterols in gram quantities was shown to interfere with cholesterol absorption and is one of the oldest pharmacological therapies for hypercholesterolemia. Although the basis for the latter was shown to be caused by exclusion of cholesterol from intestinal micelles by plant sterols, it was not until the identification of the a rare genetic disease, sitosterolemia, first described in 1974, that led to the hypothesis that specific molecular mechanism(s) governed both the entry and excretion of sterols by the body. This talk will cover the physiology of dietary sterol metabolism, genetics and pathophysiology of sitosterolemia. Additionally, the role of plant sterols in normal and abnormal metabolism in humans as well as selected animal models will be discussed.

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“…Direct sequencing of PCR amplified genomic fragments was performed as described previously [11]. The 5' flanking region, all the exons and the 3'UTR region, as well as the introns of Abcg5 and Abcg8 with size less than 1 Kb, were individually amplified using primers, as described in Table 2.…”

Section: Methodsmentioning

confidence: 99%

The rat STSL locus: characterization, chromosomal assignment, and genetic variations in sitosterolemic hypertensive rats

Pandit

Klett

et al. 2003

BMC Cardiovasc Disord

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BackgroundElevated plant sterol accumulation has been reported in the spontaneously hypertensive rat (SHR), the stroke-prone spontaneously hypertensive rat (SHRSP) and the Wistar-Kyoto (WKY) rat. Additionally, a blood pressure quantitative trait locus (QTL) has been mapped to rat chromosome 6 in a New Zealand genetically hypertensive rat strain (GH rat). ABCG5 and ABCG8 (encoding sterolin-1 and sterolin-2 respectively) have been shown to be responsible for causing sitosterolemia in humans. These genes are organized in a head-to-head configuration at the STSL locus on human chromosome 2p21.MethodsTo investigate whether mutations in Abcg5 or Abcg8 exist in SHR, SHRSP, WKY and GH rats, we initiated a systematic search for the genetic variation in coding and non-coding region of Abcg5 and Abcg8 genes in these strains. We isolated the rat cDNAs for these genes and characterized the genomic structure and tissue expression patterns, using standard molecular biology techniques and FISH for chromosomal assignments.ResultsBoth rat Abcg5 and Abcg8 genes map to chromosome band 6q12. These genes span ~40 kb and contain 13 exons and 12 introns each, in a pattern identical to that of the STSL loci in mouse and man. Both Abcg5 and Abcg8 were expressed only in liver and intestine. Analyses of DNA from SHR, SHRSP, GH, WKY, Wistar, Wistar King A (WKA) and Brown Norway (BN) rat strains revealed a homozygous G to T substitution at nucleotide 1754, resulting in the coding change Gly583Cys in sterolin-1 only in rats that are both sitosterolemic and hypertensive (SHR, SHRSP and WKY).ConclusionsThe rat STSL locus maps to chromosome 6q12. A non-synonymous mutation in Abcg5, Gly583Cys, results in sitosterolemia in rat strains that are also hypertensive (WKY, SHR and SHRSP). Those rat strains that are hypertensive, but not sitosterolemic (e.g. GH rat) do not have mutations in Abcg5 or Abcg8. This mutation allows for expression and apparent apical targeting of Abcg5 protein in the intestine. These rat strains may therefore allow us to study the pathophysiological mechanisms involved in the human disease of sitosterolemia.

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High-resolution physical and transcript map of human chromosome 2p21 containing the sitosterolaemia locus

Cited by 13 publications

References 42 publications

Sitosterolemia

Sitosterolemia

Plant sterols and stanols: Their role in health and disease

The rat STSL locus: characterization, chromosomal assignment, and genetic variations in sitosterolemic hypertensive rats

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