Common low-density lipoprotein receptor mutations in the French Canadian population.

Leitersdorf, Eran; Tobin, Evan J.; Davignon, Jean; Hobbs, Helen H.

doi:10.1172/jci114531

Cited by 288 publications

(189 citation statements)

References 33 publications

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“…The results indicate that FH may be more genetically diverse in Ontario than in Quebec. Five LDLR mutations, namely two large deletions and three missense mutations (W66G; E207K and C646Y) underlie about two-thirds of the FH cases in Quebec (Leitersdorf et al 1990). The larger number of mutations in the Ontario FH sample is consistent with the larger population of Ontario (about 12 million people) compared to Quebec (about 7.4 million people).…”

Section: Resultsmentioning

confidence: 99%

Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent

et al. 2001

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Heterozygous familial hypercholesterolemia (FH) is a relatively common autosomal dominant disorder, which is characterized by elevated plasma concentrations of low density lipoprotein (LDL) cholesterol and early coronary heart disease. FH results from mutations in the gene encoding the LDL receptor (LDLR). In Canada, there is a founder effect for LDLR mutations in FH among individuals of French descent, most of whom reside in the province of Quebec. However, the spectrum of mutations in other regions, specifically in the populous and predominantly English-speaking province of Ontario, has not been studied. We sequenced the coding regions, promoter and intron-exon boundaries of the LDLR gene in 60 Ontario FH subjects from a variety of ethnic backgrounds other than French Canadian. We found 25 LDLR mutations in 34 subjects. Eleven LDLR mutations were novel, including two in-frame deletions of a single amino acid (one each in exons 2 and 4), two larger deletions that shifted the reading frame (one each in exons 4 and 10), five missense mutations (C42R, A370T, T413M, L561P and E760D) and two splice acceptor mutations (one each in introns 3 and 8). The results indicate that FH is more genetically diverse in Ontario than in Quebec. The results are also consistent with findings from investigations of the LDLR in FH conducted in other countries, in which PCR-based, exonby-exon sequencing uncovers small mutations in about half of the subjects screened. The gap in molecular diagnosis suggests that lesions not found by this sequencing strategy, such as larger scale LDLR mutations that cannot be amplified, may underlie a substantial number of cases of FH. Alternatively, there might be genetic heterogeneity underlying the FH phenotype, with contributions from other single or multiple genes.

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Section: Resultsmentioning

confidence: 99%

Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent

et al. 2001

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“…25,29,30 Four multi-allelic markers were also tested, a polymorphism associated with an Alu sequence located within intron 15, 31 a (CA) n (D19S394), a (TAA) n (D19S594) and a (TA) n repeat located respectively flanking, in intronic sequences and in the 3' end of the LDLR gene. 32,33 The Alu sequence was amplified by PCR on a 9600 Geneamp (Perkin-Elmer Biosystems, Courtaboeuf, France) for 30 cycles (94°C for 20 s, 56°C for 20 s, 72°C for 30 s) with 20 mM of each primer, 1 mM MgCl 2 , and radiolabelled α 33 P dATP.…”

Section: Ldlr Gene Analysismentioning

confidence: 99%

Autosomal dominant type IIa hypercholesterolemia: evaluation of the respective contributions of LDLR and APOB gene defects as well as a third major group of defects

et al. 2000

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Autosomal dominant type IIa hypercholesterolaemia (ADH) is characterised by an elevation of total plasma cholesterol associated with increased LDL particles. Numerous different molecular defects have been identified in the LDL receptor (LDLR) and few specific mutations in the apolipoprotein B (APOB) gene resulting in familial hypercholesterolaemia and familial defective apoB-100 respectively. To estimate the respective contribution of LDLR, APOB and other gene defects in this disease, we studied 33 well characterised French families diagnosed over at least three generations with ADH through the candidate gene approach. An estimation of the proportions performed with the HOMOG3R program showed that an LDLR gene defect was involved in approximately 50% of the families (P = 0.001). On the other hand, the estimated contribution of an APOB gene defect was only 15%. This low estimation of ADH due to an APOB gene defect is further strengthened by the existence of only two probands carrying the APOB (R3500Q) mutation in the sample. More importantly and surprisingly, 35% of the families in the sample were estimated to be linked to neither LDLR nor APOB genes. These data were confirmed by the exclusion of both genes through direct haplotyping in three families. Our results demonstrate that the relative contributions of LDLR and APOB gene defects to the disease are very different. Furthermore, our results also show that genetic heterogeneity is, generally, underestimated in ADH, and that at least three major groups of defects are involved. At this point, the contribution of the recently mapped FH3 gene to ADH cannot be assessed nor its importance in the group of 'non LDLR / non APOB' families.

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“…PCR primers for amplification of each exon of the LDLR gene and all exon-intron boundaries were described previously by Leitersdorf et al (1990) and Leren et al (1993). Each of 35 PCR cycles consisted of 30 s at 94°C, 30s at 60°C, and 30 s at 72°C.…”

Section: Patients and Lipoprotein Measurementmentioning

confidence: 99%

Five familial hypercholesterolemic kindreds in Japan with novel mutations of the LDL receptor gene

et al. 1998

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In the course of investigations of familial coronary artery disease in Hokkaido, the northern island of Japan, we identified five families in which multiple members showed elevated plasma levels of low-density lipoprotein (LDL) cholesterol. To determine the genetic etiology of their lipoprotein abnormalities, we screened DNA samples from these families for mutations in all 18 exons and the exon-intron boundaries of the LDL receptor (LDLR) gene. Novel point mutations were identified in each family: (1) a C-to-A transversion at nucleotide 285, causing a nonsense mutation at codon 74, in eight members of family A; (2) a G-to-A transition at nucleotide 1136, causing substitution of Tyr for Cys at codon 358, in six members of family B; (3) a C-to-T transition at nucleotide 1822, causing substitution of Ser for Pro at codon 587, in five members of family C; (4) a one-base insertion of G to a five-G stretch at nucleotides 1774-1778 (codons 571-572), causing a frameshift, in six members of family D; and (5) a one-base deletion of T at nucleotide 1963-1964 (codon 634), causing a frameshift, in three members of family E. Through the molecular genetic approach a total of 28 individuals in these families were diagnosed unequivocally as heterozygous for the respective LDLR mutations. This method also helped us to diagnose familial hypercholesterolemia, or to exclude from carrier status, 11 children with borderline high cholesterol levels.

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Common low-density lipoprotein receptor mutations in the French Canadian population.

Cited by 288 publications

References 33 publications

Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent

Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent

Autosomal dominant type IIa hypercholesterolemia: evaluation of the respective contributions of LDLR and APOB gene defects as well as a third major group of defects

Five familial hypercholesterolemic kindreds in Japan with novel mutations of the LDL receptor gene

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