Multiple crm- mutations in familial hypercholesterolemia. Evidence for 13 alleles, including four deletions.

Hobbs, Helen H.; Leitersdorf, Eran; Goldstein, Joseph L.; Brown, Michael S.; Russell, David W.

doi:10.1172/jci113402

Cited by 67 publications

(26 citation statements)

References 36 publications

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“…In addition, it may be predicted that the deletion of exons 13 and 14 and the fusion of exon 12 to exon 15 during splicing leads to a frame shift in mRNA and the occurrence of a premature stop codon in exon 15. 16 A shorter mRNA was documented in the homozygous FH patient reported by Hobbs et al 17 In proband FH-29, we were unable to detect the abnormal mRNA species, presumably because the latter was present in a very low concentration. This is not surprising, as several recent reports have demonstrated that mutations affecting mRNA translation (e.g., nonsense mutations) are often associated with a decreased intracellular level of the abnormal mRNA.…”

Section: Discussioncontrasting

confidence: 46%

“…When this study was repeated using a probe complementary to exons [15][16][17] ure 3D), Bgl II, EcoRl, and EcoRV (data not shown) confirmed the presence of a larger fragment; the digestions with Kpn I, Stu I ( Figure 3E), Nco I, and Pvu II (data not shown) revealed the presence of the additional 5.5-kb fragment. These data indicated that the 5.5-kb abnormal fragments contained sequences that were specifically recognized by the exon 15-17 probe.…”

Section: Proband Fh-30mentioning

confidence: 73%

“…Bgl //, Pvu //, and Stu / and hybridized with cDNA probe A (specific for exons [15][16][17] normal counterparts. This preliminary screening suggested that FH-29 was heterozygous for a deletion located 3' to exon 12 because, by using exon-specific probes, we found that all restriction sites from exons 1-12 were maintained (data not shown).…”

Section: Figure 1 Upper Panel: Photographs Of Southern Blot Analysismentioning

confidence: 99%

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Characterization of three mutations of the low density lipoprotein receptor gene in Italian patients with familial hypercholesterolemia.

Lelli

Ghisellini

Gualdi

et al. 1991

Arterioscler Thromb

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1 FH is a heterogeneous condition, since at least four classes of functional defects have been observed that disrupt the synthesis, intracellular transport, LDL binding capacity, and internalization of the LDL-receptor complex.2 During the past few years, the availability of cDNA and genomic clones 3 " 5 has made it possible to characterize the mutations of the LDL receptor (LDL-R) gene at the DNA level. A large array of From the Istituto di Patologia Generale (NX., M.G., R.G., R.T., S.C.), Universita di Modena; Cattedra di Gerontologia (A.G., A.C.), Universita di Bologna; Istituto di Terapia Medica Sistematica (MA, S.F.), Universita di Roma "La Sapienza"; and Cattedra di Genetica Medica (D.A.C.) and Servizio Prevenzione Arteriosclerosi (S.B.), Universita di Geneva, Italia.Supported in part by a grant from the Progetto per la Ricerca Sanitaria della Regione Emilia e Romagna and partly by a grant from Squibb Italia, SpA.Address for correspondence: Sebastiano Calandra, MD, Istituto di Patologia Generale, Universita di Modena, Via Campi 287, 41100 Modena, Italy.Received January 4, 1990; revision accepted October 29, 1990. mutations, including deletions, insertions, nonsense, and missense types, have been found so far in various countries and ethnic groups. During the past 2 years, we have undertaken a survey of Italian FH patients through a collaborative study involving several lipid clinics and aimed at investigating the frequency and features of the major structural rearrangements of the LDL-R gene. So far, we have screened 23 unrelated FH families living in various districts of Italy. DNA screening conducted by the use of 10 restriction enzymes allowed us to identify three patients with gross mutations of the LDL-R gene. Qinical and biochemical details of the 23 FH patients as well as the results of DNA screening and restriction fragment length polymorphism haplotype analysis will be reported elsewhere. In the present report, we illustrate the results of the analysis of the three gross mutations. Two of them (one insertion and one deletion) are new mutations. MethodsThe patients included in this study and designated FH-29, FH-30, and FH-44 were selected from a

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Section: Discussioncontrasting

confidence: 46%

Section: Proband Fh-30mentioning

confidence: 73%

Section: Figure 1 Upper Panel: Photographs Of Southern Blot Analysismentioning

confidence: 99%

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Characterization of three mutations of the low density lipoprotein receptor gene in Italian patients with familial hypercholesterolemia.

Lelli

Ghisellini

Gualdi

et al. 1991

Arterioscler Thromb

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“…Haplotype analysis of the LDL receptor gene using 10 restriction fragment length polymorphic sites (18) suggested that TT was homozygous for the mutant LDL receptor allele (data not shown). We then used the recently described gene-amplification technique (8) to selectively amplify and sequence exon 2 of the LDL receptor gene, and we determined the nucleotide sequence of the amplified DNA by the Maxam-Gilbert technique (17).…”

Section: Discussionmentioning

confidence: 99%

Deletion in the first cysteine-rich repeat of low density lipoprotein receptor impairs its transport but not lipoprotein binding in fibroblasts from a subject with familial hypercholesterolemia.

Leitersdorf

Hobbs

Fourie

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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The ligand-binding domain of the low density lipoprotein (LDL) receptor is composed of seven cysteine-rich repeats, each -40 amino acids long. Previous studies by van Driel et al. [van Driel, I. R., Goldstein, J. L., Sudhof, T. C. & Brown, M. S. (1987) J. Biol. Chem. 262, 17443-17449] showed that if the first repeat of the ligand-binding domain (encoded by exon 2) is deleted, the receptor fails to bind an anti-LDL receptor monoclonal antibody (IgG-C7) but continues to bind LDL with high affinity. Cultured fibroblasts from a Black South African Xhosa patient (TT) with the clinical syndrome of homozygous familial hypercholesterolemia demonstrated highaffinity cell-surface binding of 125I-labeled LDL but not '25I-labeled IgG-C7. Previous haplotype analysis, using 10 restriction fragment length polymorphic sites, suggested that the patient inherited two identical LDL receptor alleles. The polymerase chain reaction technique was used to selectively amplify exon 2 of the LDL receptor gene from this patient. Sequence analysis of the amplified fragment disclosed a deletion of six base pairs that removes two amino acids, aspartic acid and glycine, from the first cysteine-rich ligand binding repeat. The mutation creates a new Pst I restriction site that can be used to detect the deletion. The existence of this mutant allele confirms that the epitope of IgG-C7 is located in the first cysteine-rich repeat and that this repeat is not necessary for LDL binding. The mutant gene produced a normally sized 120-kilodalton LDL receptor precursor protein that matured to the 160-kilodalton form at less than one-fourth the normal rate. Thus, deletion of two amino acids within the first cysteine-rich repeat retards receptor transport from the endoplasmic reticulum to the cell surface, in contrast to deletion of the entire first repeat, which has no effect on receptor maturation.Mutations in the low density lipoprotein (LDL) receptor gene result in the autosomal dominant disease familial hypercholesterolemia (FH) (1). The LDL receptor is a transmembrane protein that binds LDL and mediates its uptake into the cell. Individuals with two mutant LDL receptor alleles have profoundly fewer or no functional LDL receptors on their cell surfaces and this is associated with markedly elevated plasma LDL-cholesterol levels. These individuals develop premature coronary atherosclerosis that often leads to myocardial infarctions in early childhood. In homozygous FH, mutations in each LDL receptor allele can be either identical (a true homozygote) or different (a compound heterozygote).

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“…Os pacientes podem ser receptor negativos, expressando pouca ou nenhuma atividade do receptor de LDL, ou receptor defeituoso, levando à expressão de isotipos de LDLR com afinidade reduzida para LDL na superfície dos hepatócitos [42][43][44][45][46][47] .…”

Section: Diagnóstico Genético Da Hipercolesterolemia Familiarunclassified

I Diretriz Brasileira de Hipercolesterolemia Familiar (HF)

Pereira¹,

Gagliardi²,

Lottenberg³

et al. 2012

Arquivos Brasileiros De Cardiologia

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Multiple crm- mutations in familial hypercholesterolemia. Evidence for 13 alleles, including four deletions.

Cited by 67 publications

References 36 publications

Characterization of three mutations of the low density lipoprotein receptor gene in Italian patients with familial hypercholesterolemia.

Characterization of three mutations of the low density lipoprotein receptor gene in Italian patients with familial hypercholesterolemia.

Deletion in the first cysteine-rich repeat of low density lipoprotein receptor impairs its transport but not lipoprotein binding in fibroblasts from a subject with familial hypercholesterolemia.

I Diretriz Brasileira de Hipercolesterolemia Familiar (HF)

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