Potential Effects of NPC1L1 Polymorphisms in Protecting against Clinical Disease in a Chinese Family with Sitosterolaemia

Abstract

increased absorption and decreased biliary excretion of cholesterol (similar to plant sterols), usually have normal to moderately elevated plasma cholesterol levels, despite the downregulation of endogenous cholesterol synthesis in hepatocytes 4) . Intestinal sterol/cholesterol absorption is governed by three key transporter molecules, including the two ATP-binding cassette (ABC) half transporters, ABCG5 and ABCG8 (previously known as sterolin-1 and -2, respectively), which heterodimerise to form a sterol efflux transporter in the liver and intestine to transport sterols (cholesterol and plant sterols) and the Niemann-Pick C1-like 1 (NPC1L1) transporter, a polytopic transmembrane protein that mediates intestinal absorption of cholesterol and sterols 5) . Sitosterolaemia is caused by mutations in either ABCG5 or ABCG8 6) . It has been estimated that sitosterolaemia occurs in 1 in 5 million people, although the true Introduction Sitosterolaemia (MIM #210250) is a very rare autosomal recessive disease characterized by excessive absorption and high plasma levels (＞30-fold) of plant sterols, particularly sitosterol and campesterol, the two major plant-derived sterols 1,2) . The clinical manifestations include tendon and tuberous xanthomas and premature atherosclerotic disease as a result of sterol deposition in the skin, tendons and coronary arteries [1][2][3] . Patients with sitosterolaemia, in whom there is Sitosterolaemia is caused by mutations in either ABCG5 or ABCG8. Chinese and Japanese individuals usually have mutations in ABCG5. We herein report a known and a novel mutation in ABCG8 and their potential interaction with NPC1L1 polymorphisms in a Chinese family with sitosterolaemia. We sequenced ABCG5 and ABCG8 and measured the levels of plasma plant sterols in a 15-yearold Chinese girl with clinical sitosterolaemia (xanthomas with elevated low-density lipoprotein cholesterol (LDL-C) and plant sterols) and her apparently healthy family members. NPC1L1 was sequenced in the genetically affected sibling and other family members. A known mutation, c.490C＞T (p. Arg164 ＊ ), in exon 4 and a novel mutation, c.1949T＞G (p.Leu650Arg), in exon 13 of ABCG8 were detected in the proband and her sister, who had elevated sterols but low LDL-C levels and no xanthomas. The genetically affected sister, but not the proband, carried two additional heterozygous changes in NPC1L1 (rs2072183 C＞G, rs2301935 A＞C), which were inherited from the mother, who also had a low LDL-C level. In this study, we detected a known and a novel mutation in ABCG8 in a Chinese patient with sitosterolaemia. The same mutations were found in her clinically normal sister, suggesting that the contrasting features with the proband may be related to different variants in NPC1L1 and/or some other undetermined lipid-related genetic factors. J Atheroscler Thromb, 2014; 21:989-995.

Sitosterolemia—10 years observation in two sisters

“…Infantile epilepsy, present in patient 2, has been reported before in a single Chinese sitosterolemia patient, but a causal relationship is unclear. As well, sitosterolemia may have contributed to altered androgens and mixed hyperandrogenemia as plant sterols can serve as precursors for steroid hormones .…”

“…Also, maximum concentrations of cholesterol and of phytosterols in patient 1 were noticeably higher than in patient 2. While there are no apparent differences between patients with mutations in ABCG5 or ABCG8 , there is considerable heterogeneity in the clinical and biochemical phenotypes of patients even with identical genotypes . The cause of this variability is not known, but time of diagnosis and start of treatment may contribute.…”

“…The cause of this variability is not known, but time of diagnosis and start of treatment may contribute. Additional factors may include NPC1L1 polymorphisms leading to reduced sterol absorption and LDL‐cholesterol levels, variations in other lipid‐related genes influencing cholesterol absorption or other pathways, and differences in dietary sterol intake, the latter especially in infants consuming different diets…”

A Rare Coincidence of Sitosterolemia and Familial Mediterranean Fever Identified by Whole Exome Sequencing

“…The former mutation in the ABCG5 gene is one of the most common mutations among Asians with sitosterolemia 13) , while the latter mutation in the ABCG5 gene is considered novel. Meanwhile, both mutations in the MEFV gene identified in the proband are two of the most common mutations emia [17][18][19] . Careful monitoring and additional therapeutic approaches are needed to reduce her serum levels of sitosterol because of the unfavorable combination of hypersitosterolemia and systemic inflammatory disease, both of which have been shown to be associated with an increased risk of cardiovascular disease.…”

Management of Familial Hypercholesterolemia in Hong Kong

“…Sitosterolemia is caused by mutations in either ABCG5 or ABCG8 21) . We previously reported the potential role of NPC1L1 polymorphisms in determining the clinical manifestation of sitosterolemia in one of the cases and her genetically affected sibling 22) . Sitosterolemia can be diagnosed on the basis of demonstration of elevated plasma levels of plant presence of tendon xanthomata were needed to support the diagnosis of FH.…”