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

Lelli, Nicoletta; Ghisellini, M.; Gualdi, Rossana; Tiozzo, Roberta; Calandra, Sebastiano; Gaddi, Antonio Vittorino; Ciarrocchi, A.; Arca, Marcello; Fazio, Sergio; Coviello, D.A.

doi:10.1161/01.atv.11.2.234

Cited by 26 publications

(20 citation statements)

References 36 publications

(20 reference statements)

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“…The large deletion at the 5' end of the gene that we have observed in FH 51 is superficially similar to that described recently in an Italian patient by Lelli et al 26 (identified as FH 44 or FH Bologna). However, the 5' 29 ), but the restriction fragment patterns obtained with FH 172 differ, and blotting with exon-specific probes confirmed that exon 15 is also deleted in this patient.…”

Section: Figure 4 Southern Blots Confirming Deletions and Rearrangemsupporting

confidence: 90%

Characterization of deletions in the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom.

Sun

Webb

Gudnason

et al. 1992

Arterioscler Thromb

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A sample of 200 patients with a clinical diagnosis of heterozygous (189) or homozygous (11) familial hypercholesterolemia (FH) attending lipid clinics in the London area have been screened for the presence of major gene defects in the low density lipoprotein (LDL) receptor gene by Southern blotting of genomic DNA with specific probes. This study Is part of a project to determine the frequency of known mutations in the LDL receptor gene in this population. A new polymorphism for the enzyme Bgt II was identified by hybridization with a probe specific for the promoter plus exon 1 of the LDL receptor gene. The observed frequency of the rare allele, characterized by a Bgi II fragment of 13 kb compared with 10 kb for the common allele, was 0.08 in this group of FH patients. Several individuals who were heterozygous for the rare allele were also heterozygous for a mutation elsewhere in the LDL receptor gene that is known to cause FH. Eight different mutations, seven deletions and one duplication, were detected in a total of nine patients, accounting for 4.5% of the mutant alleles in this group. Three of the mutations are apparently identical to deletions that have been described previously in FH patients of British or European origin, while the remaining five have not been described. Two of these were in patients of Polish and Asian Indian origin, while the other three were in patients of apparently British ancestry.

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Section: Figure 4 Southern Blots Confirming Deletions and Rearrangemsupporting

confidence: 90%

Characterization of deletions in the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom.

Sun

Webb

Gudnason

et al. 1992

Arterioscler Thromb

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“…Explants were cultured in 25 cm 2 flasks in DMEM (Dulbecco's modification of Eagle's medium), 100 IU/ml of penicillin, and 50 g/ml of streptomycin, 2 mM glutamine, 15% fetal calf serum, and 95% air-5% CO 2 as previously reported (20).…”

Section: Patientsmentioning

confidence: 99%

“…The cDNA clone pHF␤A1 of human ␤-actin was used to normalize the RNA filters. Northern blots were performed as described previously (20).…”

Section: Northern Blot Analysismentioning

confidence: 99%

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Niemann-Pick type C disease

Tarugi

Ballarini

Bembi

et al. 2002

Journal of Lipid Research

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We analyzed Niemann-Pick type C disease 1 (NPC1) gene in 12 patients with Niemann-Pick type C disease by sequencing both cDNA obtained from fibroblasts and genomic DNA. All the patients were compound heterozygotes. We found 15 mutations, eight of which previously unreported. The comparison of cDNA and genomic DNA revealed discrepancies in some subjects. In two unrelated patients carrying the same mutations (P474L and nt 2972del2) only one mutant allele (P474L), was expressed in fibroblasts. The mRNA corresponding to the other allele was not detected even in cells incubated with cycloheximide. The promoter variants ( ؊ 1026T/G and ؊ 1186T/C or ؊ 238 C/G), found to be in linkage with 2972del2 allele do not explain the lack of expression of this allele, as they were also found in control subjects. In another patient, (N1156S/Q922X) the N1156S allele was expressed in fibroblasts while the expression of the other allele was hardly detectable. In a fourth patient cDNA analysis revealed a point mutation in exon 20 (P1007A) and a 56 nt deletion in exon 22 leading to a frameshift and a premature stop codon. The first mutation was confirmed in genomic DNA; the second turned out to be a T → G transversion in exon 22, predicted to cause a missense mutation (V1141G). In fact, this transversion generates a donor splice site in exon 22, which causes an abnormal pre-mRNA splicing leading to a partial deletion of this exon. In some NPC patients, therefore, the comparison between cDNA and genomic DNA may reveal an unexpected expression of some mutant alleles of NPC1

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“…9 All DNA samples were digested by using 5 to 10 U/g of several restriction enzymes, separated by agarose gel electrophoresis, transferred to nylon membranes, and hybridized with various LDL-R cDNA probes. 10 Polymerase chain reaction (PCR) amplifications of the promoter region and exons 1 to 18 of the LDL-R gene were carried out by using the primers reported by Hobbs et al 2 in a total volume of 50 L containing 100 ng of genomic DNA, 10 mmol/L Tris-HCl, 50 mmol/L KCl, 1.5 mmol/L MgCl 2 , 100 mol of each of the 4 nucleotides, 10 pmol of each primer, and 2 U of Taq DNA polymerase. Single-strand conformation polymorphism analysis was performed by using a vertical gel unit; 5 L of PCR product was mixed with an equal amount of 95% formamide, 20 mmol/L EDTA, 0.1% bromophenol blue, and 0.1% xylene cyanole; denatured at 96°C for 5 minutes; snap-cooled in 4°C ice water; and then loaded onto an 8% polyacrylamide gel containing 5% glycerol.…”

Section: Analysis Of the Ldl-r Genementioning

confidence: 99%

Clinical Expression of Familial Hypercholesterolemia in Clusters of Mutations of the LDL Receptor Gene That Cause a Receptor-Defective or Receptor-Negative Phenotype

Bertolini¹,

Cantàfora²,

Averna³

et al. 2000

ATVB

133

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Abstract-Seventy-one mutations of the low density lipoprotein (LDL) receptor gene were identified in 282 unrelated Italian familial hypercholesterolemia (FH) heterozygotes. By extending genotype analysis to families of the index cases, we identified 12 mutation clusters and localized them in specific areas of Italy. To evaluate the impact of these mutations on the clinical expression of FH, the clusters were separated into 2 groups: receptor-defective and receptor-negative, according to the LDL receptor defect caused by each mutation. These 2 groups were comparable in terms of the patients' age, sex distribution, body mass index, arterial hypertension, and smoking status. In receptor-negative subjects, LDL cholesterol was higher (ϩ18%) and high density lipoprotein cholesterol lower (Ϫ5%) than the values found in receptor-defective subjects. The prevalence of tendon xanthomas and coronary artery disease (CAD) was 2-fold higher in receptor-negative subjects. In patients Ͼ30 years of age in both groups, the presence of CAD was related to age, arterial hypertension, previous smoking, and LDL cholesterol level. Independent contributors to CAD in the receptor-defective subjects were male sex, arterial hypertension, and LDL cholesterol level; in the receptor-negative subjects, the first 2 variables were strong predictors of CAD, whereas the LDL cholesterol level had a lower impact than in receptor-defective subjects. Overall, in receptor-negative subjects, the risk of CAD was 2.6-fold that of receptordefective subjects. Wide interindividual variability in LDL cholesterol levels was found in each cluster. Apolipoprotein E genotype analysis showed a lowering effect of the ⑀2 allele and a raising effect of the ⑀4 allele on the LDL cholesterol level in both groups; however, the apolipoprotein E genotype accounted for only 4% of the variation in LDL cholesterol.Haplotype analysis showed that all families of the major clusters shared the same intragenic haplotype cosegregating with the mutation, thus suggesting the presence of common ancestors. (Arterioscler Thromb Vasc Biol. 2000;20:e41-e52.)

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

Cited by 26 publications

References 36 publications

Characterization of deletions in the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom.

Characterization of deletions in the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom.

Niemann-Pick type C disease

Clinical Expression of Familial Hypercholesterolemia in Clusters of Mutations of the LDL Receptor Gene That Cause a Receptor-Defective or Receptor-Negative Phenotype

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