Novel polypyrimidine variation (IVS46: del T -39...-46) in ABCA1 causes exon skipping and contributes to HDL cholesterol deficiency in a family with premature coronary disease.
Novel polypyrimidine variation (IVS46: del T -39...-46) in ABCA1 causes exon skipping and contributes to HDL cholesterol deficiency in a family with premature coronary disease.
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ABCA1 中的新型多嘧啶变异 (IVS46: del T -39...-46) 会导致外显子跳跃，并导致患有早发冠心病的家庭中 HDL 胆固醇缺乏。
DOI：
10.1161/01.res.0000102957.84247.8f
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Miller,Michael
中科院分区：
文献类型：
--
作者：
Hong,SeungHo;Rhyne,Jeffrey;Miller,Michael
Recent studies have implicated mutations in the ATP-binding cassette transporter A1,ABCA1, as a cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). We investigated a proband with very low levels of high-density lipoprotein cholesterol (HDL-C, 6 mg/dL) and a history of premature coronary heart disease (CHD). Sequencing of theABCA1gene revealed 2 distinct variants. The first mutation was a G5947A substitution (R1851Q). The second mutation was a single-nucleotide deletion of thymidine in a polypyrimidine tract located 33 to 46 bps upstream to the start of exon 47. This mutation does not involve the 3′ acceptor splice site and is outside the lariat branchpoint sequence (IVS46: del T −39…−46). Amplification of cDNA obtained in cultured fibroblasts of the proband and affected family member revealed an abnormally spliced cDNA sequence with skipping of exon 47. These variants were not identified in over 400 chromosomes of healthy whites. Compound heterozygotes (n=4) exhibited the lowest HDL-C (11±5 mg/dL) and ApoA-I (35±15 mg/dL) compared with wild-type (n=25) (HDL-C 51±14 mg/dL; ApoA-I 133±21 mg/dL) (P<0.0005) or subjects affected with either R1851Q (n=6) (HDL-C 36±8; ApoA-I 117±19) or IVS46: del T −39…−46 (n=5) (HDL-C 31+9; ApoA-I 115+28 (P<0.01). These data suggest that polypyrimidine tract variation may represent a novel mechanism for altered splicing and exon skipping that is independent of traditional intronic variants as previously identified in acceptor/donor splice regions or the lariat branchpoint domain.
