Screening for mutations in exon 4 of the LDL receptor gene in a German population with severe hypercholesterolemia

Geisel, J.; Holzem, Guido; Oette, K.

doi:10.1007/bf00210411

Cited by 21 publications

(18 citation statements)

References 8 publications

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“…Mutation analysis performed previously in German FH patients revealed the presence of several different LDLR gene mutations (Schuster et al, 1993a(Schuster et al, , b, 1995Geisel et al, 1995). The identification of mu- tations R329X, R395Q, and 558insG in German FH patients analysed in this study contributes to a more complete knowledge of the mutational spectrum in this heterogeneous population.…”

supporting

confidence: 62%

Two novel and two known low-density lipoprotein receptor gene mutations in German patients with familial hypercholesterolemia

et al. 1998

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supporting

confidence: 62%

Two novel and two known low-density lipoprotein receptor gene mutations in German patients with familial hypercholesterolemia

et al. 1998

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“…In addition to the 8-bp duplication identified in the Costa Rican family, duplications of 21 bp (Hobbs et al 1992) and 18 bp (Geisel et al 1995;Kotze et al 1995 b), have previously been described in the corresponding region of the LDLR gene. To our knowledge, no two independently derived duplications involving several base pairs have previously been reported at an identical location within the same gene.…”

Section: Resultsmentioning

confidence: 85%

Mutation analysis reveals an insertional hotspot in exon 4 of the LDL receptor gene

et al. 1996

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Mutation analysis of the low density lipoprotein receptor (LDLR) gene revealed a novel 8-bp duplication after nucleotide 681 in a Costa Rican patient with familial hypercholesterolaemia. The frameshift caused by this mutation results in a premature termination codon in the EGF precursor homology domain of the mature LDLR, whereby a truncated protein of the first 206 residues with an additional 39 abnormal residues would be created. The insertion overlaps with previously described duplications of 18 bp and 21 bp, thus revealing an insertional hotspot in exon 4 of the LDLR gene. We propose that the structural features of this region of the LDLR gene contribute significantly to genetic instability and the subsequent DNA duplication via an endogenous sequence-directed mechanism of mutagenesis.

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“…The C660X mutation is also called the "Lebanese" allele (Lehrman et al 1987;Oppenheim et al 1991): all five Ontario FH subjects with this mutation could trace their ancestry to the Mediterranean basin, the Middle East or Lebanon. The 652delG mutation has been found in subjects from many different ethnic backgrounds (Hobbs et al 1992;Gudnason et al 1993;Giesel et al 1995;Day et al 1997): the Ontario FH subject with this mutation had ancestry from the British Isles. The C6W and E207K mutations have been found in subjects from many different ethnic backgrounds (Hobbs et al 1992;Day et al 1997): all subjects in the Ontario FH sample with these mutations had northern European ancestry.…”

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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Screening for mutations in exon 4 of the LDL receptor gene in a German population with severe hypercholesterolemia

Cited by 21 publications

References 8 publications

Two novel and two known low-density lipoprotein receptor gene mutations in German patients with familial hypercholesterolemia

Two novel and two known low-density lipoprotein receptor gene mutations in German patients with familial hypercholesterolemia

Mutation analysis reveals an insertional hotspot in exon 4 of the LDL receptor gene

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

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