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外显子组测序、ANGPTL3 突变与家族性混合型高脂血症。

Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.

机构信息

Cardiovascular Research Center, Massachusetts General Hospital, and Department of Medicine, Boston University School of Public Health, Boston, MA 02114, USA.

出版信息

N Engl J Med. 2010 Dec 2;363(23):2220-7. doi: 10.1056/NEJMoa1002926. Epub 2010 Oct 13.

DOI:10.1056/NEJMoa1002926
PMID:20942659
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3008575/
Abstract

We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.).

摘要

我们对两名血脂过低合并症患者（其特征为极低的低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和甘油三酯水平）的全基因组蛋白编码区（“外显子组”）进行了测序。这两名患者均为载脂蛋白 L3（编码血管生成素样蛋白 3）两个不同无意义突变的复合杂合子。已有研究报告称，ANGPTL3 可抑制脂蛋白脂肪酶和内皮脂肪酶，从而增加啮齿动物的血浆甘油三酯和高密度脂蛋白胆固醇水平。我们发现的 ANGPTL3 突变表明该基因在人类 LDL 胆固醇代谢中具有重要作用，并显示外显子组测序在鉴定遗传性疾病的新遗传病因方面的有效性。（由国家人类基因组研究所等资助）。

相似文献

[1]
Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.

N Engl J Med. 2010-10-13

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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[3]
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[4]
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[6]
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[7]
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[8]
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[9]
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本文引用的文献

[1]
Biological, clinical and population relevance of 95 loci for blood lipids.

Nature. 2010-8-5

[2]
Exome sequencing identifies the cause of a mendelian disorder.

Nat Genet. 2009-11-13

[3]
Genetic diagnosis by whole exome capture and massively parallel DNA sequencing.

Proc Natl Acad Sci U S A. 2009-10-27

[4]
Targeted capture and massively parallel sequencing of 12 human exomes.

Nature. 2009-9-10

[5]
Identification of a new functional domain in angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) involved in binding and inhibition of lipoprotein lipase (LPL).

J Biol Chem. 2009-5-15

[6]
Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing.

Nat Biotechnol. 2009-2

[7]
Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans.

J Clin Invest. 2009-1

[8]
Evidence for a quantitative trait locus affecting low levels of apolipoprotein B and low density lipoprotein on chromosome 10 in Caucasian families.

J Lipid Res. 2007-12

[9]
Hepatic proprotein convertases modulate HDL metabolism.

Cell Metab. 2007-8

[10]
Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase.

Arterioscler Thromb Vasc Biol. 2007-2

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