Journal
CIRCULATION RESEARCH
Volume 93, Issue 10, Pages 1006-1012Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000102957.84247.8F
Keywords
ABCA1; HDL cholesterol deficiency; mutation; polypyrimidine
Funding
- NHLBI NIH HHS [HL-61369] Funding Source: Medline
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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 the ABCA1 gene 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; poA-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.
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