Compound heterozygous mutations in ABCG5 or ABCG8 causing Chinese familial Sitosterolemia

Sun, Weiwei; Zhang, Tian; Zhang, Xiaoguang; Wang, Jieyu; Chen, Yuqing; Long, Yun; Zhang, Gong; Wang, Yajian; Chen, Ye; Fang, Tony; Chen, Mingwu

doi:10.1002/jgm.3185

Cited by 8 publications

(8 citation statements)

References 28 publications

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“…In patients with lipid disorders, lipoprotein (a) [Lp(a)] is an independent risk factor for cardiovascular disease [28]. High Lp(a) levels have been related to worse cardiovascular prognosis [29], However, Lp(a) was normal in the four patients described here and other reported patients [21].…”

Section: Discussionmentioning

confidence: 67%

“…Most previous studies [12,[14][15][16][17][18]21] were case reports, and most of the Chinese patients did not have data on treatment and follow-up. Currently, there is no study summarizing the clinical characteristics and gene mutation types of Chinese sitosterolemia patients.…”

Section: Comparisons With Other Studies and What Does The Current Wor...mentioning

confidence: 99%

“…To expand the knowledge and reported information regarding clinical experiences related to sitosterolemia, the natural history and follow-up assays for four sitosterolemia children were traced and reported here. Literature review on clinical presentation and molecular characteristics of a total of 55 Chinese patients was conducted by collecting information from accessible databases, as well as internet sources, such as PubMed, Wiper database, Baidu Scholar, China National Knowledge Infrastructure (CNKI), and Wanfang Data [12][13][14][15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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Features of chinese patients with sitosterolemia

Zhou

Su²,

Cai³

et al. 2022

Lipids Health Dis

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Background Sitosterolemia is a lipid disorder characterized by the accumulation of phytosterols in plasma and organs, caused by mutations in the ABCG5 and/or ABCG8 genes. The disease is frequently misdiagnosed and mistreated as familial hypercholesterolemia (FH). To gain a better understanding of the disease, the current status of diagnosis and treatment of Chinese patients with sitosterolemia was reviewed and summarized. Method Literature search was performed. The clinical features and molecular characteristics of Chinese patients with sitosterolemia were analysed. Four children with sitosterolemia and the treatment experience were described. Results Fifty-five patients with sitosterolemia have been reported in China. These patients were aged from 3 months to 67 years at diagnosis, and the median was 8 years of age. Several complications, such as xanthomas in 47 patients (85%), thrombocytopenia in 17 patients (31%), anemia in 14 patients (25%), and cardiovascular damage in 12 patients (22%), were observed. Thirty-nine patients (71%) exhibited mutations in the ABCG5 gene, 15 patients (27%) showed mutations in ABCG8, and variations in both genes occurred in one patient (2%). A patient with two clinically rare diseases, namely, sitosterolemia and glycogen storage disease type VI (GSD VI)), is reported here for the first time. The four reported patients were treated with low cholesterol and phytosterol-limited diet alone or combined with cholestyramine. Even though decreases were observed for total plasma cholesterol (TC) and low-density-lipoprotein cholesterol (LDL-C), and these levels were as low as normal in some patients, the levels of plant sterols remained above the normal range. However, TC, LDL-C and plant sterol levels remained at high levels in patients treated with a control diet control only. Conclusions The analysis reveals that different from Caucasians carrying mainly variations in ABCG8, most Chinese patients have mutations in the ABCG5 gene, and Arg446Ter, Gln251Ter, anArg389His might be hot-spot mutations in Chinese patients. The current survey provides clinical data to enable the development of a standardized protocol for the diagnosis and treatment of sitosterolemia in China.

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Section: Discussionmentioning

confidence: 67%

Section: Comparisons With Other Studies and What Does The Current Wor...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Features of chinese patients with sitosterolemia

Zhou

Su²,

Cai³

et al. 2022

Lipids Health Dis

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“…(35) In humans, mutations in ABCG5/8 cause a rare condition called sitosterolemia, a recessive disorder characterized by sterol accumulation secondary to reduced biliary and intestinal sterol excretion and premature coronary atherosclerosis as well as liver injury. (36)(37)(38) In a case report, a patient with sitosterolemia and two mutations in ABCG8 underwent liver transplant for cirrhosis and had significant correction of elevated serum phytosterol levels following transplantation. (36) This case demonstrates both the important role for canalicular rather than intestinal excretion of phytosterols by ABCG5/8, and the hepatic toxicity of retained phytosterols that can lead to progressive liver disease.…”

Section: F E Dmentioning

confidence: 99%

NF‐κB Regulation of LRH‐1 and ABCG5/8 Potentiates Phytosterol Role in the Pathogenesis of Parenteral Nutrition–Associated Cholestasis

et al. 2021

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BaCKgRoUND aND aIMS: Chronically administered parenteral nutrition (PN) in patients with intestinal failure carries the risk for developing PN-associated cholestasis (PNAC). We have demonstrated that farnesoid X receptor (FXR) and liver X receptor (LXR), proinflammatory interleukin-1 beta (IL-1β), and infused phytosterols are important in murine PNAC pathogenesis. In this study we examined the role of nuclear receptor liver receptor homolog 1 (LRH-1) and phytosterols in PNAC.

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“…Some patients with sitosterolemia have no xanthoma and only show blood system changes, such as hemolytic anemia and thrombocytopenia. This is often misdiagnosed as idiopathic thrombocytopenia and EVANS syndrome, or even splenectomy ( 27 ). Therefore, for the diagnosis of sitosterolemia, it is not only necessary to proceed from clinical manifestations but also to improve the detection of plasma phytosterols, the morphological analysis of blood cells, and genetic diagnosis ( 27 ).…”

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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Compound heterozygous mutations in ABCG5 or ABCG8 causing Chinese familial Sitosterolemia

Cited by 8 publications

References 28 publications

Features of chinese patients with sitosterolemia

Features of chinese patients with sitosterolemia

NF‐κB Regulation of LRH‐1 and ABCG5/8 Potentiates Phytosterol Role in the Pathogenesis of Parenteral Nutrition–Associated Cholestasis

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

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