Characterization and geographic distribution of the low density lipoprotein receptor (LDLR) gene mutations in northwestern Greece

Abstract

Familial Hyperholesterolaemia (FH) is a clinical syndrome characterised by elevated serum total cholesterol levels due to an increase in low density lipoprotein (LDL) cholesterol, by tendon xanthomata and clinical manifestations of ischaemic heart disease in early life. Typically, it results from mutations in the low-density lipoprotein receptor (LDLR) gene. So far, over 600 mutations have been reported for the LDLR gene and account for FH. The nature of LDLR gene mutations is different in various ethnicities and has also regional distribution within each ethnicity. Eleven mutations have already been described in the Greek population. This report describes seven LDLR gene mutations accounting for FH in Northwestern Greece (81T>G, 517T>C, 858C>A, 1285G>A, 1352T>C, 1646G>A and 1775G>A) and their geographic distribution. We have recently described one of these mutations (1352T>C) as a novel point mutation in a Greek family originating from Northwestern Greece. Furthermore, two previously identified mutations (81T>C, 1775G>A) were also detected in the Greek FH patients for the first time. The 1775G>A mutation was responsible for all the homozygous patients in our area, indicating a founder effect. These data will favor the development of tailed information and screening programs in Northwestern Greece for the primary prevention of cardiovascular disease in FH patients.

Intronic mutations outside of Alu -repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia

“…Mutations causing FH are usually detected by denaturing gradient gel electrophoresis (DGGE), single-strand conformation polymorphism (SSCP), or denaturing high performance liquid chromatography (Bertolini et al 2000;Bunn et al 2002;Ebhardt et al 1999;Ekström et al 1998;Graham et al 1999;Hattori et al 1999;Heath et al 2001;Jensen et al 1996;Kuhrova et al 2001;Lombardi et al 2000;Loux et al 1992;Mak et al 1998;Mozas et al 2000;Nauck et al 2001;Nissen et al 1996), and by DNA sequencing of polymerase chain reaction (PCR) products (Hobbs et al 1992;Leitersdorf et al 1990). In particular populations, oligonucleotide ligation assay (Baron et al 1996) and allele-specific oligonucleotides (Miltiadous et al 2001) have been used to detect known mutations. Despite the large number of mutations identified, many authors report that 1/3 to 3/4 of FH patients are not LDLR mutation carriers.…”

Original research Characterization of low density lipoprotein receptor (LDLR) gene mutations in Albania

“…The mutation was first described in Americans [8] and also in Croatian and English FH patients [Database of LDLR gene mutations in FH: http://www.ucl.ac.uk/fh]. Furthermore, the mutation 81T>G has also been previously described in the population of northwestern Greece [9]. …”

LDL-receptor mutations in Europe

“…Scanning for unknown mutations causing FH has been done using DGGE, SSCP, or DHPLC [Bertolini et al, 2000;Bunn et al, 2002;Ebhardt et al, 1999;Ekström et al, 1995;Graham et al, 1999;Hattori et al, 1999;Heath et al, 2001;Kuhrova et al, 2001;Lombardi et al, 2000;Loux et al, 1992;Mak et al, 1998;Mozas et al, 2000;Nauck et al, 2001;Nissen et al, 1996], as well as DNA sequencing of PCR-amplified products [Hobbs et al, 1992;Leitersdorf et al, 1989]. In particular populations, oligonucleotide ligation assay [Baron et al, 1996] and allele-specific oligonucleotides [Miltiadous et al, 2001] have been used to detect known mutations. The methodology for mutation detection has been improved by high-throughput SSCP analysis .…”

“…The p.G549D [G528D] mutation is most common among Greek FH patients [Traeger-Synodinos et al, 1998;Miltiadous et al, 2001;Dedoussis et al, 2004], accounting for 16.4% of the FH population studied. The next most common LDLR mutation is c.1285G4A (p.V429M [V408M]) in exon 9 (14.9%), and the third is c.858C4A (p.S286R [S265R]) in exon 6 (9.9%).…”