title: Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia.
abstract: BACKGROUND
  Familial hypercholesterolemia is a human monogenic disease caused by population-specific mutations in the low density lipoprotein (LDL) receptor gene. Despite thirteen different mutations of the LDL receptor gene were reported from Russia prior to 2003, the whole spectrum of disease-causing gene alterations in this country is poorly known and requires further investigation provided by the current study.
  
  
  METHODS
  Forty-five patients with clinical diagnosis of FH were tested for the apolipoprotein B (apoB) mutation R3500Q by restriction fragment length analysis. After exclusion of R3500Q mutation high-sensitive fluorescent single-strand conformation polymorphism (SSCP) analysis and automatic DNA sequencing were used to search for mutations in the LDL receptor gene.
  
  
  RESULTS
  We found twenty one rare sequence variations of the LDL receptor gene. Nineteen were probably pathogenic mutations, and two (P518P, T705I) were considered as neutral ones. Among the mutations likely to be pathogenic, eight were novel (c.670-671insG, C249X, c.936-940del5, c.1291-1331del41, W422X, c.1855-1856insA, D601N, C646S), and eleven (Q12X, IVS3+1G>A, c.651-653del3, E207X, c.925-931del7, C308Y, L380H, c.1302delG, IVS9+1G>A, V776M, V806I) have already been described in other populations. None of the patients had the R3500Q mutation in the apoB gene.
  
  
  CONCLUSIONS
  Nineteen pathogenic mutations in the LDL receptor gene in 23 probands were identified. Two mutations c.925-931del7 and L380H are shared by St.-Petersburg population with neighbouring Finland and several other mutations with Norway, Sweden or Denmark, i.e. countries from the Baltic Sea region. Only four mutations (c.313+1G>A, c.651-653del3, C308Y and W422X) were recurrent as all those were found in two unrelated families. By this study the number of known mutations in the LDL receptor gene in St.-Petersburg area was increased nearly threefold. Analysis of all 34 low density lipoprotein receptor gene mutations found in St.-Petersburg argues against strong founder effect in Russian familial hypercholesterolemia.
authors.affiliation: Department of Molecular Genetics, Institute of Experimental Medicine, St-Petersburg, Russia. f.zakharova@vz5518.spb.edu
authors.forename: Faina M
authors.initials: FM
authors.lastname: Zakharova
authors.forename: Dorte
authors.initials: D
authors.lastname: Damgaard
authors.forename: Michail Y
authors.initials: MY
authors.lastname: Mandelshtam
authors.forename: Valery I
authors.initials: VI
authors.lastname: Golubkov
authors.forename: Peter H
authors.initials: PH
authors.lastname: Nissen
authors.forename: Gitte G
authors.initials: GG
authors.lastname: Nilsen
authors.forename: Anette
authors.initials: A
authors.lastname: Stenderup
authors.forename: Boris M
authors.initials: BM
authors.lastname: Lipovetsky
authors.forename: Vladimir O
authors.initials: VO
authors.lastname: Konstantinov
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Denisenko
authors.forename: Vadim B
authors.initials: VB
authors.lastname: Vasilyev
authors.forename: Ole
authors.initials: O
authors.lastname: Faergeman
mesh_terms: D001055:Apolipoproteins B / Q000235:genetics; D001483:Base Sequence; D018389:Codon, Nonsense; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D005820:Genetic Testing; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D011973:Receptors, LDL / Q000235:genetics*; D012426:Russia
chemical_list: D001055:Apolipoproteins B; D018389:Codon, Nonsense; D011973:Receptors, LDL; D004247:DNA