Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene.

Screening for structural alterations of the low density lipoprotein (LDL) receptor gene by Southern blot analysis revealed an abnormal band pattern in one subject with a clinical diagnosis of homozygous familial hypercholesterolemia (FH). The molecular defect was further characterized by polymerase chain reaction and cDNA sequencing. These analyses identified a 4.8 kb in-frame deletion of exons 2 and 3, where exon 1 was spliced to exon 4. This deletion is expected to produce a receptor that has lost the two first cysteine-rich repeats of the ligand-binding domain. Previously published data of in vitro site-directed mutagenesis has shown that binding of LDL to such a receptor is reduced to 70% of normal. A mild phenotype in our FH homozygote is consistent with that observation. In contrast, heterozygotes carrying this deletion have a relatively more severe phenotype that is comparable to that of heterozygotes carrying a null-allele. A severe phenotype was also found in a compound heterozygote carrying this deletion. Possible mechanisms for this phenotypic variability are discussed.-Rødningen, O. K., S. Tonstad, J. D. Medh, D. A. Chappell, L. Ose, and T. P. Leren. Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene.

[Diagnosis and treatment of severe hyperlipidemia]. / Diagnose og behandling av svaer hyperlipidemi.

Though severe hyperlipidaemia (total cholesterol level > or = 13 mmol/l in this study) is uncommon, it is important to make a precise diagnosis. We examined 57 patients with isolated severe hypercholesterolaemia. Of these, four were homozygotes for familial hypercholesterolaemia, 48 were heterozygotes for familial hypercholesterolacmia and one had sitosterolemia. The heterozygotes carried 15 different LDL receptor mutations, with no one mutation predominating. When the diagnosis is made, relatives should be given the opportunity to be tested. Combined severe hyperlipidaemia is usually due to a secondary cause, at our clinic, the most common cause is diabetes mellitus. The underlying disease should be treated first. However, many patients will require additional lipid-lowering drugs because the underlying disease may be associated with an increased risk of cardiovascular disease. With the exception of fish oil capsules, drugs that reduce serum triglyceride levels substantially are not registered in Norway at present.

Studies of serum lipids in hypercholesterolaemic rabbits treated with doxazosin.

Serum lipids were studied in hypercholesterolaemic rabbits treated with the selective alpha 1-adrenoreceptor antagonist doxazosin. Hypercholesterolaemia had been induced by cholesterol feeding which raised mean (+/- SEM) total serum cholesterol from 1.4 (+/- 0.1) mmol/l to 84.1 (+/- 3.6) mmol/l. A cross-over design was used to compare the effect of doxazosin with placebo in 20 rabbits of which 16 completed the study. Doxazosin (2 mg/kg) or placebo vehicle was administered subcutaneously once daily for three weeks. Compared with placebo, doxazosin produced an 8.6% greater reduction in total serum cholesterol. This difference did not, however, reach statistical significance.