Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia

Nauck, Matthias; Köster, Wolfgang; Dörfer, K.; Eckes, J.; Scharnagl, Hubert; Gierens, H.; Nissen, Henrik; Wieland, Heinrich; März, Winfried

doi:10.1002/humu.1171

Cited by 37 publications

(19 citation statements)

References 31 publications

(28 reference statements)

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“…Non-conservative Found with p.C696W (predicted to be pathogenic) in this report (Salazar et al 2002). Non-conservative Suggest that as this variant, like T726I, alters the attachment site for O-linked carbohydrate chains, it may also therefore be non-pathogenic (Nauck et al 2001). …”

Section: G374s G353smentioning

confidence: 64%

Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia Database

Leigh

Foster

Whittall

et al. 2008

Annals of Human Genetics

209

195

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SummaryFamilial hypercholesterolemia (FH) (OMIM 143890) is most commonly caused by variations in the LDLR gene which encodes the receptor for Low Density Lipoprotein (LDL) cholesterol particles. We have updated the University College London (UCL) LDLR FH database (www.ucl.ac.uk/ldlr) by adding variants reported in the literature since 2001, converting existing entries to standard nomenclature, and transferring the database to the Leiden Open Source Variation Database (LOVD) platform. As of July 2007 the database listed 1066 unique LDLR gene events. Sixty five percent (n = 689) of the variants are DNA substitutions, 24% (n = 260) small DNA rearrangements (<100bp) and 11% (n = 117) large DNA rearrangements (>100bp), proportions which are similar to those reported in the 2001 database (n = 683, 62%, 24% and 14% respectively). The DNA substitutions and small rearrangements occur along the length of the gene, with 24 in the promoter region, 86 in intronic sequences and 839 in the exons (93 nonsense variants, 499 missense variants and 247 small rearrangements). These occur in all exons, with the highest proportion (20%) in exon 4 (186/949); this exon is the largest and codes for the critical ligand binding region, where any missense variant is likely to be pathogenic. Using the PolyPhen and SIFT prediction computer programmes 87% of the missense variants are predicted to have a deleterious effect on LDLR activity, and it is probable that at least 48% of the remainder are also pathogenic, but their role in FH causation requires confirmation by in vitro or family studies.

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Section: G374s G353smentioning

confidence: 64%

Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia Database

Leigh

Foster

Whittall

et al. 2008

Annals of Human Genetics

209

195

View full text Add to dashboard Cite

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“…The mutations detected in our sample are summarized in Table 2. Three of the mutations (367T>A, 377T>A, and 917C>A) are described for the first time and the rest (858C>A and 1301C>T) have been previously found in other populations (Hobbs et al 1992;Webb et al 1996;Day et al 1997;Mavroidis et al 1997;Nauck et al 2001;Wang et al 2001). These nucleotide changes constitute four missense mutations (S102T, F105Y, S265R, and T413M) and one nonsense mutation (S285X).…”

Section: Resultsmentioning

confidence: 79%

Screening for point mutations in the LDL receptor gene in Bulgarian patients with severe hypercholesterolemia

et al. 2004

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Familial hypercholesterolemia (FH) is a common, autosomal dominant disorder of lipid metabolism, caused by defects in the receptor-mediated uptake of LDL (low-density lipoproteins) due to mutations in the LDL receptor gene (LDLR). Mutations underlying FH in Bulgaria are largely unknown. The aim of the present study was to provide information about the spectrum of point mutations in LDLR in a sample of 45 Bulgarian patients with severe hypercholesterolemia. Exons 3, 4, 6, 8, 9, and 14, previously shown to be mutational hot spots in LDLR, were screened using PCR-single-strand conformation polymorphism (SSCP). Samples with abnormal SSCP patterns were sequenced. Three different, hitherto undescribed point mutations (367T>A, 377T>A, 917C>A) and two previously described mutations (858C>A and 1301C>T) in eight unrelated patients were identified; four of the detected point mutations being missense mutations and one, a nonsense mutation. One of the newly described point mutations (917C>A) is a base substitution at a nucleotide position, at which two other different base substitutions have already been reported. Thus, all three possible base substitutions at this nucleotide position have been detected, making it a hot spot for point mutations causing FH. This is the first such mutational hot spot described in exon 6 of LDLR.

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“…Among them one was an homozygous substitution in the promoter region, 16 were missense mutations (p.C95S, p.C109R, p.C143Y, p.C155G, p.C216Y, p.Q254P, p.D266N, p.A391T, p.E408K, p.R416W, p.V429M, p.V523M, p.G592E, p.A606S, p.V653F, p.C711S), 2 were nonsense mutations (p.W305X, p.E317X), 3 were small deletions and insertions (c.680_681delAC, c.661_662insCCCCG, c.680_681insGGACAAATCTGA), and 2 were splice site mutations (c.313+1G>A, c.313+2T>C). The majority of these mutations have been reported before in the German population (Ebhardt et al, 1999;Nauck et al, 2001). Three of the mutations detected are novel.…”

Section: Mutations In the German Fh Patientsmentioning

confidence: 86%

Molecular characterization of familial hypercholesterolemia in German and Greek patients

et al. 2004

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We used the denaturing gradient gel electrophoresis (DGGE) method to define mutations in the promoter region, the 18 exons, and their flanking intronic sequences of the low-density lipoprotein (LDL) receptor gene LDLR, causing familial hypercholesterolemia (FH) phenotype in 100 German and in 100 Greek hypercholesterolemic individuals. In addition, we tested all patients for the presence of mutations in codons 3456-3553 of the gene encoding apolipoprotein B-100 (APOB). Twenty-six aberrant DGGE patterns were identified and subsequently directly sequenced. In LDLR, two novel missense mutations (c.1957G>T/p.V653F, c.647 G>A/p.C216Y) and one novel homozygous base substitution c.1-156 C>T in the repeat 2 of the promoter region were identified among German FH patients; one novel splice site c.1060+10C>G was identified among Greek FH patients. One of the German FH patients was a carrier for the mutations c.1171G>A/p.A391T and p.V653F, and two of the Greek FH patients were compound heterozygotes for the mutations c.1150C>T/p.Q384X and c.1158C>G/p.D386E. Two German FH patients carried the mutation p.R3500Q within APOB. Comparing the mutations within the LDLR gene of the two European FH populations, the German population seems to be more heterogeneous than the Greek cohort. Further studies in progress are trying to elucidate the responsiveness to drug therapy in association with LDLR genotype and the nutritional habits of the two FH populations.

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Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia

Cited by 37 publications

References 31 publications

Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia Database

Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia Database

Screening for point mutations in the LDL receptor gene in Bulgarian patients with severe hypercholesterolemia

Molecular characterization of familial hypercholesterolemia in German and Greek patients

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