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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1864.)
© 2001 American Heart Association, Inc.

Letters to the Editor

Donor Splice-Site Mutation (210+1G_C) in the ApoB Gene Causes a Very Low Level of ApoB-100 and LDL Cholesterol

Francine K. Welty; Kristin A. Guida; Jennifer J. Andersen

Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts

To the Editor:

Apolipoprotein (apo) B, the main protein in LDL, exists in 2 isoforms in plasma: apoB-100, which is produced in the liver, and apoB-48, which is a naturally occurring truncation of apoB-100 and is secreted in the intestine in response to dietary fat. Heterozygous subjects for hypobetalipoproteinemia (HBLP), an autosomal codominant disorder, have LDL cholesterol (C) levels between 0.52 and 1.29 mmol/L (20 to 50 mg/dL) and are asymptomatic.¹ In contrast, homozygous and compound heterozygous subjects have levels of LDL-C that range from undetectable to <0.26 mmol/L (10 mg/dL) and have variable clinical symptoms including retinitis pigmentosa, fat malabsorption, acanthocytosis, ataxia, and debilitating neurological diseases.¹ The reasons for the variability in clinical symptoms have been unclear. Welty et al² previously reported an asymptomatic, 54-year-old subject heterozygous for an apoB-44.4 truncation who had an undetectable plasma level of LDL-C and a very low level of apoB-100, findings suggesting that he was a compound heterozygote with a second apoB gene mutation. To locate this mutation, we amplified the entire apoB gene by using polymerase chain reaction (PCR) primers and reaction conditions as previously described.³ The PCR products were purified and sequenced by using PCR priming oligonucleotides. Sequencing revealed a G-to-C transition at the first nucleotide of the donor splice site of intron 1 (210+1G_C) in the proband and a son (Figure).

View larger version (19K): [in this window] [in a new window]   Figure 1. DNA sequence of splicing mutation in intron 1. Of 10 clones, 6 contained the normal apoB sequence (left), and 4 contained a G-to-C transition at the first nucleotide . . . [Full Text of this Article]

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