Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8

Williams, Kori; Segard, Allison; Graf, Gregory A.

doi:10.3390/ijms22052641

Cited by 30 publications

(16 citation statements)

References 149 publications

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“…ABCG5 and ABCG8 together encode a heterodimeric ATP-binding cassette transporter that facilitates secretion of cholesterol and non-cholesterol sterols in the intestine and bile. High plasma campesterol levels might compete with cholesterol for ABCG5/ABCG8 transporters during biliary cholesterol secretion, resulting in decreased biliary cholesterol levels and reduced risk of gallstones 49 , 50 (Supplementary Fig. 10 ).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

et al. 2022

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Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.

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Section: Resultsmentioning

confidence: 99%

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

et al. 2022

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“…Hayato Tada suggested that sitosterolemia can be diagnosed if the following conditions are all met at the same time ( 25 ): (1) clinical manifestations (xanthoma of skin or tendon); (2) laboratory tests (serum sitosterol ≥1 mg/dl); (3) familial hypercholesterolemia and cerebrotendinous xanthomatosis are excluded; (4) pathogenic mutations ABCG5 or ABCG8 . But the clinical manifestations of sitosterolemia are highly heterogeneous, although the genotype and phenotype lack an obvious correlation, and most laboratories lack conditions for phytosterol determination ( 26 ). Thus, at present, the diagnosis of this disease remains very difficult.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Analysis of a Family With Sitosterolemia Caused by a Novel ATP-Binding Cassette Subfamily G Member 5 Compound Heterozygous Mutation

Shen

Chen

et al. 2022

Front. Cardiovasc. Med.

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Sitosterolemia (OMIM ##210250), also known as phytosterolemia, is a rare autosomal recessive disorder caused by mutations in the ATP-binding cassette subfamily G member 5 (ABCG5) or member 8 (ABCG8) genes. This leads to abnormal functions of the transporter sterolin-1 protein encoded by ABCG5 and sterolin-2 protein encoded by ABCG8, respectively, which can hinder the formation of stable ABCG5/G8 heterodimers, decreasing its ability to transport sterols. As a result, phytosterols in tissue or plasma are significantly increased, leading to early onset atherosclerosis-related diseases and xanthelasma of tendons and skin. In this study, whole exome sequencing was performed on a Chinese Han proband with sitosterolemia to capture the target gene and screen for suspected pathogenic mutations. Sanger sequencing of the family members was performed to verify the relationship between family genetics and phenotypes. The structural and functional changes in the transporter sterolin-1 protein after the responsible mutation were predicted using bioinformatics analysis. A novel compound heterozygous mutation in the ABCG5 gene (NM_022436) was identified in a proband with sitosterolemia, one of which was inherited from the father: c.296T >G (p.M99R), and one from the mother: c.−76 C >T. SIFT, Polyphen2, and Mutation Taster software predicted that p.M99R may be the responsible variant and a novel variant. RNAFold software predicts that c.−76 C >T may affect the transcriptional information or the binding of RNA binding proteins by regulating the structure of RNA, and ultimately affect gene transcription or RNA stability and translation. Swiss model software predicts that the amino acid sequence around p.M99R is highly conserved, and p.M99R leads to instability of the tertiary structure of the ABCG5/ABCG8 heterodimer. GPS 5.0 predicted that M99R affects the phosphorylation of nearby amino acid sequences, and DUET and VarSite software predicted that M99R affects the stability of sterolin-1 and cause disease. The p.M99R and c.−76 C >T mutations led to the formation of unstable heterodimers, which disturbed sterol absorption and excretion in vivo. The compound heterozygous variants c.296 T >G (p.m99r) and C.−76 C >T on exon 3 of ABCG5 in this family may be the molecular genetic basis of sitosterolemia.

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Section: Campesterol and Gallstones: Potential Causal Link Gallstones Affect 10-20%mentioning

confidence: 99%

Genome-wide association study of 1,391 plasma metabolites in 6,136 Finnish men identifies 303 novel signals and provides biological insights into human diseases

Yin

Chan

Bose

et al. 2021

Preprint

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Few studies have explored the impact of rare variants (minor allele frequency, MAF<1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1,391 plasma metabolites in 6,136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.

show abstract

Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8

Cited by 30 publications

References 149 publications

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

Clinical and Genetic Analysis of a Family With Sitosterolemia Caused by a Novel ATP-Binding Cassette Subfamily G Member 5 Compound Heterozygous Mutation

Genome-wide association study of 1,391 plasma metabolites in 6,136 Finnish men identifies 303 novel signals and provides biological insights into human diseases

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