title: Analysis of sequence variations in low-density lipoprotein receptor gene among Malaysian patients with familial hypercholesterolemia.
abstract: BACKGROUND
  Familial hypercholesterolemia is a genetic disorder mainly caused by defects in the low-density lipoprotein receptor gene. Few and limited analyses of familial hypercholesterolemia have been performed in Malaysia, and the underlying mutations therefore remain largely unknown.We studied a group of 154 unrelated FH patients from a northern area of Malaysia (Kelantan). The promoter region and exons 2-15 of the LDLR gene were screened by denaturing high-performance liquid chromatography to detect short deletions and nucleotide substitutions, and by multiplex ligation-dependent probe amplification to detect large rearrangements.
  
  
  RESULTS
  A total of 29 gene sequence variants were reported in 117(76.0%) of the studied subjects. Eight different mutations (1 large rearrangement, 1 short deletion, 5 missense mutations, and 1 splice site mutation), and 21 variants. Eight gene sequence variants were reported for the first time and they were noticed in familial hypercholesterolemic patients, but not in controls (p.Asp100Asp, p.Asp139His, p.Arg471Gly, c.1705+117 T>G, c.1186+41T>A, 1705+112C>G, Dup exon 12 and p.Trp666ProfsX45). The incidence of the p.Arg471Gly variant was 11%. Patients with pathogenic mutations were younger, had significantly higher incidences of cardiovascular disease, xanthomas, and family history of hyperlipidemia, together with significantly higher total cholesterol and low density lipoprotein levels than patients with non-pathogenic variants.
  
  
  CONCLUSIONS
  Twenty-nine gene sequence variants occurred among FH patients; those with predicted pathogenicity were associated with higher incidences of cardiovascular diseases, tendon xanthomas, and higher total and low density lipoprotein levels compared to the rest. These results provide preliminary information on the mutation spectrum of this gene among patients with FH in Malaysia.
authors.affiliation: Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.
authors.forename: Alyaa
authors.initials: A
authors.lastname: Al-Khateeb
authors.forename: Mohd K
authors.initials: MK
authors.lastname: Zahri
authors.forename: Mohd S
authors.initials: MS
authors.lastname: Mohamed
authors.forename: Teguh H
authors.initials: TH
authors.lastname: Sasongko
authors.forename: Suhairi
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Zurkurnai
authors.initials: Z
authors.lastname: Yusof
authors.forename: Bin A
authors.initials: BA
authors.lastname: Zilfalil
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D001483:Base Sequence; D002318:Cardiovascular Diseases / Q000150:complications; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D005091:Exons; D005260:Female; D017353:Gene Deletion; D015321:Gene Rearrangement; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000097:blood; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014973:Xanthomatosis / Q000150:complications
chemical_list: D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D002784:Cholesterol