Analysis of the low density lipoprotein receptor gene (LDLR) mutation spectrum in Russian familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a very common human hereditary disease in Russia and in the whole world with most of mutations localized in the gene coding for the low density lipoprotein receptor (LDLR). The object of this review is to systematize the knowledge about LDLR mutations in Russia. With this aim we analyzed all available literature on the subject and tabulated the data. More than 1/3 (80 out of 203, i. e. 39.4 %) of all mutations reported from Russia were not described in other populations. To date, most LDLR gene mutations have been characterized in large cities: Moscow (130 entries), Saint Petersburg (50 entries), Novosibirsk (34 mutations) and Petrozavodsk (19 mutations). Other regions are poorly studied. The majority of pathogenic mutations (142 out of 203 reported here or 70 %) were revealed in single pedigrees; 61 variants of mutations were described in two or more genealogies; only 5 mutations were found in 10 or more families. As everywhere, missense mutations prevail among all types of nucleotide substitutions in LDLR, but the highest national specificity is imparted by frameshift mutations: out of 27 variants reported, 19 (or 70 %) are specific for Russia. The most abundant in mutations are exons 4 and 9 of the gene due to their largest size and higher occurrence of mutations in them. Poland,the Czech Republic, Italy and the Netherlands share the highest number of mutations with the Russian population. Target sequencing significantly accelerates the characterization of mutation spectra in FH, but due to the absence of systematic investigations in the regions, one may suggest that most of LDLR mutations in the Russian population have not been described yet.

Cholesterol Levels in Genetically Determined Familial Hypercholesterolaemia in Russian Karelia.

Familial hypercholesterolaemia (FH) is a rare disease that tends to be diagnosed lately. In Russia, the genetic and phenotypic characteristics of the disease are not well defined. We investigated 102 patients with definite FH. In 52 of these patients (50.9%) genetic analysis was performed, revealing pathogenic mutations of the low density lipoprotein (LDL) receptor gene in 22 patients. We report here five mutations of the LDL receptor gene found in the Karelian FH sample for the first time. The detection rate of mutations in definite FH patients was 42.3%. Two groups of patients with a definite diagnosis of FH according to the Dutch Lipid Clinic Network criteria were compared: the first group had putatively functionally important LDL receptor gene mutations, while in the second group LDL receptor gene mutations were excluded by single-strand conformation polymorphism analysis. Total and LDL cholesterol levels were higher in the group with LDL receptor mutations compared to the mutation-free population. The frequency of mutations in patients with LDL cholesterol > 6.5 mmol/L was more than 3 times higher than that in patients with LDL < 6.5 mmol/L. Total and LDL cholesterol levels and the frequency of coronary heart disease and myocardial infarction were higher in the group with definite FH compared to groups with probable and possible FH. Cholesterol figures in FH patients of different age and sex from the Karelian population were comparable.

[The Familial Hypercholesterolemia Caused by a Novel Human Low Density Lipoprotein Receptor Gene Mutation c.1327 T>C (p.W433R)].

During investigation of molecular nature of familial hypercholesterolemia (FH) in Petrozavodsk (Russia) cohort of patients a novel low density lipoprotein (LDL) receptor gene mutation was found. This mutation designated c.1327 T>C (W443R [W422R]) was predicted to cause substitution of arginine for tryptophan residue in the very conservative -propeller domain of the LDL receptor. Inheritance of the new mutation was traced in four generations and its cosegregation with hypercholesterolemia phenotype was observed. Despite the predicted pathogenic effect of the mutation, ischemic heart disease in the pedigree was mild or absent. We consider identification of this mutation in the pedigree extremely helpful to start preventive medical treatment in affected patients.

"Finnish" mutations in LDL receptor gene: a rare cause of familial hypercholesterolemia in St. Petersburg and Petrozavodsk.

The search for two mutations, FH-Helsinki and FH-North Karelia, in LDL receptor gene was carried out in patients with familial hypercholesterolemia from St. Petersburg (80 families) and Petrozavodsk (80 families) using allele-specific PCR and analysis of single-stranded DNA fragment conformation polymorphism (SSCP analysis) with subsequent sequencing. The FH-North Karelia mutation was found in one family in St. Petersburg and in one family in Petrozavodsk, while FH-Helsinki mutation was not detected in any of the samples. Hence, the two "Finnish" mutations together responsible for 2/3 familial hypercholesterolemia cases in Finland were extremely rare in the Russian regions neighboring Finland.

[New mutations in low-density lipoprotein receptor gene in familial hypercholesterolemia patients from Petrozavodsk].

Using an automated fluorescent single-strand conformation polymorphism (SSCP) analysis of the entire coding region, promoter zone, and exon-intron junctions of the low-density lipoprotein (LDL) receptor gene, we examined 80 DNA samples of patients with familial hypercholesterolemia (FH) from Petrozavodsk. We revealed mutations that might cause FH in five probands, including FH-North Karelia (c.925-931del7) mutation and four previously unknown mutations. These novel mutations included a transversion (c.618T>G (p.S206R), one nucleotide insertion c.195_196insT (p.FsV66:D129X), a complex gene rearrangement c.192del10/ins8 (p.FsS65:D129X), and a single nucleotide deletion c.2191delG (p.FsV731:V736X). Three out of four novel mutations produce an open reading frame shift and the premature termination of translation. An analysis of the cDNA sequence of the LDL receptor showed that this might result in the formation of a transmembrane-domain-deficient receptor that is unable to bind and internalize the ligand. Our results suggest the absence of a strong founder effect associated with FH in the Petrozavodsk population.