Genetic analysis and functional study of a novel ABCG5 mutation in sitosterolemia with hematologic disease

Wanzi Jiang; Yiwen Xu; Zhenzhen Fu; Moran Hu; Qinyi Wu; Yong Ji; John Zhong Li; Yingyun Gong; Hongwen Zhou

doi:10.1016/j.gene.2023.147596

Genetic analysis and functional study of a novel ABCG5 mutation in sitosterolemia with hematologic disease

Gene. 2023 Aug 30:879:147596. doi: 10.1016/j.gene.2023.147596. Epub 2023 Jun 28.

Authors

Wanzi Jiang¹, Yiwen Xu¹, Zhenzhen Fu¹, Moran Hu¹, Qinyi Wu¹, Yong Ji², John Zhong Li³, Yingyun Gong⁴, Hongwen Zhou⁵

Affiliations

¹ Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University and Jiangsu Province Hospital, Nanjing, China.
² Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China; The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Suzhou, China.
³ The Key Laboratory of Rare Metabolic Disease, Department of Biochemistry and Molecular Biology, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
⁴ Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University and Jiangsu Province Hospital, Nanjing, China. Electronic address: gongyingyun@njmu.edu.cn.
⁵ Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University and Jiangsu Province Hospital, Nanjing, China. Electronic address: drhongwenzhou@njmu.edu.cn.

PMID: 37390873
DOI: 10.1016/j.gene.2023.147596

Abstract

Sitosterolemia is a rare autosomal recessive hereditary disease caused by loss-of-function genetic mutations in either ATP-binding cassette subfamily G member 5 or member 8 (ABCG5 or ABCG8). Here, we investigate novel variants in ABCG5 and ABCG8 that are associated with the sitosterolemia phenotype. We describe a 32-year-old woman with hypercholesterolemia, tendon and hip xanthomas, autoimmune hemolytic anemia and macrothrombocytopenia from early life, which make us highly suspicious of the possibility of sitosterolemia. A novel homozygous variant in ABCG5 (c.1769C>A, p.S590X) was identified by genomic sequencing. We also examined the lipid profile, especially plant sterols levels, using gas chromatography-mass spectrometry. Functional studies, including western blotting and immunofluorescence staining, showed that the nonsense mutation ABCG5 1769C>A hinders the formation of ABCG5 and ABCG8 heterodimers and the function of transporting sterols. Our study expands the knowledge of variants in sitosterolemia and provides diagnosis and treatment recommendations.

Keywords: ABCG5; Gene mutation; Hematological disorders; Lipid profile; Sitosterolemia.

Publication types

Case Reports

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 5 / genetics
Adult
Female
Humans
Hypercholesterolemia* / complications
Hypercholesterolemia* / genetics
Lipid Metabolism, Inborn Errors* / complications
Lipid Metabolism, Inborn Errors* / diagnosis
Lipid Metabolism, Inborn Errors* / genetics
Lipoproteins / genetics
Mutation
Phytosterols* / adverse effects
Phytosterols* / genetics
Thrombocytopenia* / genetics

Substances

Lipoproteins
ATP Binding Cassette Transporter, Subfamily G, Member 5
Phytosterols
ABCG5 protein, human

Supplementary concepts

Sitosterolemia