Novel Donor Splice Site Mutation of ABCG5 Gene in Sitosterolemia

Lam, Ching‐Wan; Cheng, Anna Wai-Fun; Tong, Sui-Fan; Chan, Yan-Wo

doi:10.1006/mgme.2001.3285

Cited by 21 publications

(15 citation statements)

References 4 publications

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“…Like our subject, most Asian probands with sitosterolemia, particularly those of Japanese origin, had mutations in ABCG5 (21)(22)(23)(24)(25)(26)(27). In this ethnic group, ABCG5 exon 9 is most commonly affected, and the most common mutation is R389H.…”

Section: Discussionmentioning

confidence: 50%

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Phenotypic heterogeneity of sitosterolemia

Wang

Joy

Mymin

et al. 2004

Journal of Lipid Research

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Sitosterolemia is a rare autosomal recessive disorder of lipoprotein metabolism characterized by xanthomas and increased plasma concentrations of plant sterols, such as sitosterol. Causative mutations occur in either the ABCG5 or ABCG8 gene, each of which encodes a sterol half-transporter expressed in the intestine. We report five Canadian subjects with nonsense mutations in these half-transporters: four related Caucasian subjects were homozygous for the ABCG8 S107X mutation, and one unrelated Japanese-Canadian subject was homozygous for a complex insertion/deletion (I/D) mutation in ABCG5 exon 3. A female subject with each mutation was symptomatic with coronary atherosclerosis: a 5-year-old ABCG8 S107X homozygote and a 75-year-old ABCG5 exon 3 I/D homozygote; these represent the extreme ends of the spectrum of vascular involvement in sitosterolemia. The largest reductions in plasma concentrations of sitosterol and LDL-cholesterol were seen with ezetimibe or bile acid sequestrant treatment, and less dramatic reductions were seen with statin drug treatment. These findings extend the range of clinical phenotypes in sitosterolemia caused by nonsense mutations in either ABCG5 or

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Section: Discussionmentioning

confidence: 50%

“…They are expressed primarily in the liver and in-testine (21)(22)(23). Since the discovery of these two genes, several mutations responsible for sitosterolemia have been described (21)(22)(23)(24)(25)(26)(27). We present two contrasting mutations in subjects with sitosterolemia.…”

Section: Sitosterolemia [Mendelian Inheritance In Man (Mim)mentioning

confidence: 98%

Phenotypic heterogeneity of sitosterolemia

Wang

Joy

Mymin

et al. 2004

Journal of Lipid Research

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“…One member of the family, ABCG5, has been implicated as an etiological agent in motor neuron disease. Mutations in ABCG5 and ABCG8 have been found in sitosterolemic patients, but those subjects do not develop motor neuron disease (11)(12)(13)(14)(15)(16). Similarly, mice in which ABCG5 and ABCG8 have been inactivated develop sitosterolemia but not motor neuron disease (17).…”

mentioning

confidence: 99%

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

Kim¹,

Fan²,

Gabbi³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

129

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Administration of ␤-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXR␤ ؊/؊ mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra. In mice at 5 months of age, ␤-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXR␤ ؊/؊ mice. WT mice were not affected by these doses of ␤-sitosterol. In 5-month-old mice, levels of the intestinal transporters, ABCG5/8 and Niemann-Pick C1 Like 1, were not affected by loss of liver X receptor (LXR) ␤ and/or treatment with ␤-sitosterol nor were there changes in plasma levels of cholesterol or ␤-sitosterol. In 8-monthold LXR␤ ؊/؊ mice there was activation of microglia in the substantia nigra pars reticulata and aggregates of ubiquitin and TDP-43 in the cytoplasm of large motor neurons in the lumbar spinal cord. Brain cholesterol concentrations were higher in LXR␤ ؊/؊ than in their WT counterparts, and treatment with ␤-sitosterol reduced brain cholesterol in both WT and LXR␤ ؊/؊ mice. In LXR␤ ؊/؊ mice but not in WT mice levels of 24-hydrocholesterol were increased upon ␤-sitosterol treatment. These data indicate that multiple mechanisms are involved in the sensitivity of LXR␤ ؊/؊ mice to ␤-sitosterol. These include activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol.central nervous system ͉ cholesterol ͉ microglia ͉ neurodegenerative disease ͉ nuclear receptor

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“…Similarly, only mutations in ABCG5 but not ABCG8, were found to be responsible for sitosterolaemia in two previously reported local cases 10,11) and in five cases reported from Taiwan 9) . However, among the present cases of sitosterolaemia, we found one known mutation (p.Arg164 ＊ ) in exon 4, and a novel mutation, p.Leu650Arg, in exon 13 of ABCG8.…”

Section: Discussionmentioning

confidence: 75%

“…Caucasians usually carry mutations in ABCG8, whereas Chinese and Japanese patients are more likely to have mutations in ABCG5 8,9) . Several mutations in ABCG5 responsible for sitosterolaemia in Chinese individuals have been described [9][10][11] . We herein report a novel mutation in ABCG8 in a 15-year-old Chinese girl with clinical sitosterolaemia and her apparently normal sibling and discuss how polymorphisms in NPC1L1 may modify the manifestations of the disease.…”

Section: Introductionmentioning

confidence: 99%

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

Yuen

Kwok

et al. 2014

JAT

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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.

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Novel Donor Splice Site Mutation of ABCG5 Gene in Sitosterolemia

Cited by 21 publications

References 4 publications

Phenotypic heterogeneity of sitosterolemia

Phenotypic heterogeneity of sitosterolemia

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

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

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