Abstract
BACKGROUND: Familial hypercholesterolemia (FH) is a human monogenic disease induced by a variety of mutations with striking genetic diversity. Despite this variability recurrent mutations occur in each population studied, which allows both elucidating prevalent mutations and developing DNA diagnostic tools for the disease. Recent research of FH in St. Petersburg, Moscow and Novosibirsk (major cities in Russia) demonstrates that each megapolis has its own FH mutation spectrum sharing only small part of mutations with other populations in Russia and Europe. In order to optimize molecular-genetic diagnostic protocols for FH in Russia we studied mutation spectrum in other regions including Petrozavodsk, a smaller town in relatively close proximity to St. Petersburg. METHODS: The principal method was automated detection of single-strand conformation polymorphism followed by direct PCR amplified DNA sequencing. RESULTS: Twelve different mutations of the low density lipoprotein (LDL) receptor gene were detected in the Petrozavodsk sample (80 patients). Out of these twelve mutations, seven have never been described before (c.192_201delinsGGACTTCA, c. 195_196insT, c. 618 T > G, c. 1340C > G, c. 1686_1693delinsT, c. 1936C > A, c. 2191delG). Other five mutations (c. 58G > A, c. 925_931del, c. 1194C > T, c. 1532 T > C, c. 1920C > T) were previously characterized elsewhere. All new mutations are considered to be a probable cause of the FH in their carriers. Direct evidence of the neutral character of c.58G > A or p. (Gly20Arg) is provided for the first time. Each pathogenic mutation was a trait of its own unique pedigree and so far has not been found in other patients. CONCLUSIONS: Strikingly, out of twelve mutations characterized in the Petrozavodsk sample only one mutation, c. 925_931del, has previously been found in patients from St. Petersburg and Finland (most closely located studied populations), suggesting some common roots in origin of these populations in the past or limited gene exchange between them nowadays. No recurrent mutations were detected.