Haplotype analysis of the low density lipoprotein receptor (LDLR) gene was performed in Norwegian subjects heterozygous for familial hypercholesterolemia (FH). Southern blot analysis of genomic DNA, using an exon 18 specific probe and the restriction enzyme NcoI, showed that two out of 57 unrelated FH subjects had an abnormal 3.6 kb band. Further analyses revealed that this abnormal band was due to a 9.6 kb deletion that included exons 16 and 17. The 5' deletion breakpoint was after 245 bp of intron 15, and the 3' deletion breakpoint was in exon 18 after nucleotide 3390 of cDNA. Thus, both the membrane-spanning and cytoplasmatic domains of the receptor had been deleted. A polymerase chain reaction (PCR) method was developed to identify this deletion among other Norwegian FH subjects. As a result of this screening one additional subject was found out of 124 subjects screened. Thus, three out of 181 (1.7%) unrelated Norwegian FH subject possessed this deletion. The deletion was found on the same haplotype in the three unrelated subjects, suggesting a common mutagenic event. The deletion is identical to a deletion (FH-Helsinki) that is very common among Finnish FH subjects. However, it is not yet known whether the mutations evolved separately in the two countries.
Cerebrotendinous xanthomatosis (CTX) is a hereditary disorder, which is inherited as an autosomally recessive disease, causing production of cholesterol and cholestanol xanthomas and mental retardation. The disease is caused by mutations in the gene for sterol 27-hydroxylase (CYP27A1). The only CTX patients diagnosed in Scandinavia are two Norwegian sisters from a consanguineous marriage. Here we have characterized the mutation and its functional consequences for the enzyme. Analysis of genomic DNA from cultured fibroblasts identified a base exchange C > T in position 1441, causing arginine at amino acid position 441 to be replaced by tryptophan. The same mutation was introduced by mutagenesis in the complimentary DNA (cDNA) for CYP27, ligated into the expression vector pcDNA4/HisMax and transfected into HEK293 cells. The mutated enzyme had less than 5% of the enzyme activity compared with the native enzyme. No abnormal catalytic products could be identified in the cell culture medium. Probably the mutation affects the haem binding within the holoenzyme. The mutation has also previously been reported in a Japanese family. This is the second example of a CTX-causing mutation that has been recognized in more than one population.
BACKGROUND: Familial hypercholesterolemia (FH) is one of the most common genetic metabolic disorders and is associated with a high risk of premature coronary heart disease. Primary prevention directed at lifestyle changes, combined with preventive medical treatment, is the most important way to reduce the risk of coronary heart disease in individuals with FH. Knowledge about the condition and adherence to drug treatment may facilitate reaching treatment goals. OBJECTIVE: The purpose of this study was to describe disease knowledge and adherence to treatment in patients with FH. SUBJECTS AND METHODS: Seventy-four patients, more than 18 years of age, with FH were asked to participate. A questionnaire on disease knowledge about FH and adherence to drug treatment was sent to the patients. Response rate was 92% (n = 68). Drug treatment, laboratory results, blood pressure, and smoking were also documented. RESULTS: Most patients knew about cholesterol, prevention, and the reason for drug treatment but were less informed about the risk of genetic transmission and family history. No significant correlation was found between knowledge and low-density lipoprotein cholesterol level. A significant, negative correlation between adherence and low-density lipoprotein cholesterol level was found (r = -.354, P