title: The molecular basis of familial hypercholesterolaemia in Turkish patients.
abstract: Familial hypercholesterolaemia (FH) is an autosomal dominant disorder of lipoprotein metabolism. In the majority of patients FH is caused by mutations in the gene for the low-density lipoprotein receptor (LDLR), and to date more than 700 mutations have been reported worldwide. In this study, 36 paediatric patients with a clinical diagnosis of FH (20 homozygous and 16 heterozygotes) were screened for mutations in the LDLR gene. Each exon, with intron-exon junctions, was screened by capillary fluorescent SSCP (F-SSCP) and heteroduplex analysis. Samples showing different band patterns were sequenced. Ten novel (including three frame shift small deletions or insertions) and seven known mutations were detected. A total of 37 out of the predicted 56 FH-causing alleles were identified (66.1%). No patients with the R3500Q mutation in the APOB gene were found. W556R was the most common mutation, explaining 21.4% of the predicted defective LDLR alleles. The novel sequence changes were deemed to be pathogenic if they altered a conserved amino acid (L143P, D147E, Q233H-C234G, C347G) or occurred in or close to a splice site (IVS 16+5) and were absent in DNA from 50 healthy Turkish subjects. These data confirm the genetic heterogeneity of FH in Turkey, and demonstrate the usefulness of F-SSCP for mutation detection.
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College London Medical School, London WC1E 6JJ, UK.
authors.forename: M Mert
authors.initials: MM
authors.lastname: Sözen
authors.forename: Ros
authors.initials: R
authors.lastname: Whittall
authors.forename: Cihan
authors.initials: C
authors.lastname: Oner
authors.forename: Ayşegül
authors.initials: A
authors.lastname: Tokatli
authors.forename: H Serap
authors.initials: HS
authors.lastname: Kalkanoğlu
authors.forename: Ali
authors.initials: A
authors.lastname: Dursun
authors.forename: Turgay
authors.initials: T
authors.lastname: Coşkun
authors.forename: Reyhan
authors.initials: R
authors.lastname: Oner
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016368:Frameshift Mutation; D017353:Gene Deletion; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D011973:Receptors, LDL / Q000235:genetics*; D014421:Turkey
chemical_list: D011973:Receptors, LDL