Identification of the serine-156 to leucine mutation in the low-density lipoprotein receptor in a German family with familial hypercholesterolemia

Schuster, Herbert; Ostwald, Philipp; Keller, Pierre-Frédéric; Wolfram, G.; Keller, C.

doi:10.1007/bf00180002

Cited by 5 publications

(3 citation statements)

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“…In addition to E256K, the Spanish allele carries another mutation, W(-18)X, in the signal peptide, that is not present in the Cuban allele, which would suggest that the W(-18)X mutation appeared later. The S156L mutation that we have identified has been previously described in different populations (Hobbs et al, 1989;Gudnason et al, 1993b;Schuster et al, 1993;Lombardi et al, 1995). This substitution occurs in a CpG dinucleotide, which is considered as a hot spot mutation site (Cooper and Krawczak, 1990).…”

Section: Discussionsupporting

confidence: 67%

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

et al. 1998

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We used the single strand conformation polymorphism (SSCP) method to investigate 13 apparently unrelated Spanish patients with familial hypercholesterolemia (FH) for mutations in the promoter region and the 18 exons and their flanking intron sequences of the low density lipoprotein (LDL) receptor gene. We found 16 aberrant SSCP patterns, and the underlying mutations were characterized by DNA sequencing. Five novel missense mutations, Q71E, C74G, C95R, C281Y and D679E, and one nonsense mutation, Q133X, were identified. We also found six missense mutations, S156L, D200Y, D200G, E256K, T413K and C646Y, and one stop codon mutation, W(-18)X, that were previously described in patients from other populations. A new frameshift mutation, 2085del19, was found in one patient. We also identified three splicing mutations; two of them are novel mutations, 1706-10G->A and 2390-1G->A, and the other one has been reported recently, 313+1G->C. Four patients were found to carry two different mutations in the same allele: Q71E and 313+1G->C; C95R and D679E; W(-18)X and E256K, and C281Y and 1706-10G->A. Our results demonstrate that there is a broad spectrum of mutations in the LDL receptor gene in the Spanish population.

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Section: Discussionsupporting

confidence: 67%

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

et al. 1998

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“…CysAEstop at 146 NL, AT, GB (Heath et al 2001;Lassel et al 1999;Lombardi et al 1995) 23 (Day et al 1997;Gorski et al 1998;Heath et al 2001;Lombardi et al 1995;Mozas et al 2000;Pimstone et al 1997;Schuster et al 1993a 26 TGTAECGT at 550 C163R CysAEArg at 163 NL, SY, CN (Heath et al 2001;Lombardi et al 2000;Pimstone et al 1998 (Giesel et al 1995;Gorski et al 1998;Heath et al 2001;Lassel et al 1999;Reshef et al 1996) 33 GACAEGGC at 662 (Bertolini et al 2000;Giesel et al 1995;Graham et al 1999;Heath et al 2001;Hobbs et al 1992;…”

Section: C146xmentioning

confidence: 97%

The molecular basis of familial hypercholesterolemia in The Netherlands

et al. 2001

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Mutations in the low-density lipoprotein (LDL) receptor gene are responsible for familial hypercholesterolemia (FH). At present, more than 600 mutations in this gene are known to underlie FH. However, the array of mutations varies considerably in different populations. Therefore, the delineation of essentially all LDL-receptor gene mutations in a population is a prerequisite for the implementation of nation-wide genetic testing for FH. In the Netherlands, mutation analysis by denaturing gradient gel electrophoresis and sequencing in 1641 clinically diagnosed FH patients resulted in the characterization of 159 different LDL-receptor gene defects. The nine most common mutations were responsible for 66.5% of our FH index cases. Of these, four mutations occurred with relatively high frequencies in specific parts of the Netherlands. The remaining mutations were only encountered in single FH patients, comprising 22.2% of the patient cohort analyzed. Subsequent genetic testing of relatives of the index cases within the national FH screening program resulted in the identification of 5,531 FH patients in total. The analysis for LDL-receptor mutations is a continuing effort to update the LDL-receptor mutation catalogue. Subsequently, with the newly generated index cases, the screening program can be extended and continued to identify and treat FH patients as early as possible and reduce cardiovascular morbidity and mortality in these patients at high risk.

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“…This mutation has now been identified in patients in the United Kingdom [15], France, (Benlian et al, unpublished), and in Germany by Dr. Schuster and his colleagues [69]. The mutation is known to abolish the binding of apoB to the LDL-R, but apoE-containing lipoproteins are bound with near normal efficiency [23].…”

Section: Range Of Expression Of Fhmentioning

confidence: 99%

European workshop on LDL receptor defects

Schuster

Humphries

1994

Clin Investig

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The first European workshop on low-density lipoprotein (LDL) receptor defects in familial hypercholesterolaemia (FH) was held in Munich in November 1993 and was attended by 35 clinical scientists from 17 different countries. The aims of the meeting were to exchange information about techniques to identify patients with the disorder, to examine progress in mutation detection in the different countries, and to establish a collaborative framework to enable genotype-phenotype comparisons to be made by comparing and contrasting results from different countries. In this report, recent recommendations for mutation nomenclature [3] have been used. LDL receptor defects in familial hypercholesterolaemiaFH is a common inherited disease showing an autosomal dominant pattern of inheritance [13]. It is characterized clinically by elevation in the concentration of LDL cholesterol in blood, tendon xanthomata and an increased risk of myocardial infarction. Familial hypercholesterolaemia is present in 5-10% of individuals who develop coronary artery disease (CAD) under the age of 55 years in the United Kingdom and United States and is therefore the best understood single-gene cause of Abbreviations: CAD = coronary artery disease; FH = familial hypercholesterolaemia; apo = apolipoprotein; PCR = polymerase chain reaction; LDL = low-density lipoprotein; LDL-R = LDL receptor; SSCP = single-strand conformation polymorphism; D D G E = denaturing gradient gel electrophoresis; RFLP = restriction fragment length polymorphism Correspondence to: H. Schuster hyperlipidaemia and thus atherosclerosis risk. The hyperlipidaemia of these patients is responsive to treatment by diet and drugs, and such treatment reduces subsequent morbidity and mortality. Children who have inherited two defective alleles of the DL receptor (LDL-R; homozygous FH, but usually compound heterozygous for two different defects) represent 1/million of the population. In these children there is usually little useful lowering of plasma LDL cholesterol levels in response to diet or drugs, and many suffer a major coronary event in the first or second decade of life, but life expectancy can be extended by appropriate treatment. Current treatment is usually by plasma exchange or LDL apheresis [28], but patients have also been treated by transplantation of a donor liver, possibly in conjunction with a heart transplant [75] and recently by ex vivo gene transfer to hepatocytes [14].

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Identification of the serine-156 to leucine mutation in the low-density lipoprotein receptor in a German family with familial hypercholesterolemia

Cited by 5 publications

References 19 publications

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

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

The molecular basis of familial hypercholesterolemia in The Netherlands

European workshop on LDL receptor defects

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