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M Pocovi

Publications and source records attributed to M Pocovi.

At least 19 recordsLinked to original sources
PubMed2005

High frequency of APOB gene mutations causing familial hypobetalipoproteinaemia in patients of Dutch and Spanish descent.

BACKGROUND: Familial hypobetalipoproteinaemia (FHBL) is an autosomal co-dominant hereditary disorder of lipoprotein metabolism characterised by decreased low density lipoprotein (LDL) cholesterol and apolipoprotein B (APOB) plasma levels. High levels of plasma APOB and LDL cholesterol are strong predictors for risk of cardiovascular disease (CVD), while individuals with low APOB and LDL cholesterol levels are thought to have lower than average risk for CVD, and in fact, heterozygous FHBL patients appear to be asymptomatic. METHODS: Rather than identifying truncated APOB proteins in plasma fractions separated by gel electrophoresis, which will miss any mutations in proteins smaller than 30 kb, we analysed the APOB gene directly, using PCR. RESULTS: We identified nine different mutations, six of which are novel. Each mutation showed complete co-segregation with the FHBL phenotype in the families, and statistically significant differences between carriers and non-carriers were found for plasma total, LDL, and HDL cholesterol, triglycerides, and APOB levels, but not for APOA1 levels. All carriers of an APOB mutation were completely free from CVD. CONCLUSIONS: Prolonged low levels of LDL cholesterol and elevated levels of HDL cholesterol may reduce the progression of atherosclerotic disease, but this has not been unequivocally shown that this is indeed the case in individuals with FHBL, and is the subject of a current study.

Adolescent↗
PubMed2002

A double mutant [N543H+2393del9] allele in the LDL receptor gene in familial hypercholesterolemia: effect on plasma cholesterol levels and cardiovascular disease.

Familial hypercholesterolemia is a genetic disorder caused by mutations in the LDL receptor gene. During a survey of mutations of LDL receptor gene in Spanish FH patients we found two mutations in the same allele: a missense N543H mutation in exon 11 and a 9bp inframe deletion (2393del9) located in exon 17. This double mutant allele was founded in 10 out of 458 unrelated patients: one homozygous FH [N543H+2393del9] + [N543H+2393del9], one compound heterozygote [N543H+2393del9] + [W-18X+E256K] and 8 heterozygotes. Flow cytometric analysis showed a defective LDL binding (20% of normal value) and internalization (23%) in lymphocytes from the homozygous patient; furthermore, studies of mitogen-stimulated lymphocytes demonstrated that the ability of LDL to support cell proliferation was impaired. Unexpectedly, not all carriers of the double mutant allele develop hypercholesterolemia and, furthermore, cholesterol-lowering treatment of the homozygous patient resulted in a 58% LDL cholesterol reduction. In conclusion, the phenotypic expression in the homozygous and heterozygous patients presented here, as well as the LDL-receptor residual activity, allowed the classification of this mutation as mild extending the group of mild mutations found at homozygosity.

Adult↗
PubMed2001

Enhanced fractional catabolic rate of apo A-I and apo A-II in heterozygous subjects for apo A-I(Zaragoza) (L144R).

We have recently reported a new apolipoprotein (apo) A-I variant (apo A-I(Zaragoza) L144R) in a Spanish family with HDL-C levels below the 5th percentile for age and sex and low apo A-I concentrations. All the apo A-I(Zaragoza) subjects were heterozygous and none of them showed evidence of coronary artery disease (CAD). Mean plasma HDL-C, apo A-I, and apo A-II levels were lower in apo A-I(Zaragoza) carriers as compared to control subjects (40, 60, and 50%, respectively). Lipid composition analysis revealed that apo A-I(Zaragoza) carriers had HDL particles with a higher percentage of HDL triglyceride and a lower percentage of HDL esterified cholesterol as compared to those of control subjects. Lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate of apo A-I(Zaragoza) carriers were normal. Apo A-I and apo A-II metabolic studies were performed on two heterozygous apo A-I(Zaragoza) carriers and on six control subjects. We used a primed constant infusion of [5,5,5-2H3]leucine and HDL apo A-I and apo A-II tracer/tracee ratios were determined by gas chromatography mass spectrometry and fitted to a monoexponential equation using SAAM II software. Both subjects carrying apo A-I(Zaragoza) variant showed mean apo A-I fractional catabolic rate (FCR) values more than two-fold higher than mean FCR values of their controls (0.470+/-0.0792 vs. 0.207+/-0.0635 x day(-1), respectively). Apo A-I secretion rate (SR) of apo A-I(Zaragoza) subjects was slightly increased compared with controls (17.32+/-0.226 vs. 12.76+/-3.918 mg x kg(-l) x day(-1), respectively). Apo A-II FCR was also markedly elevated in both subjects with apo A-I(Zaragoza) when compared with controls (0.366+/-0.1450 vs. 0.171+/-0.0333 x day(-1), respectively) and apo A-II SR was normal (2.31+/-0.517 vs. 2.1+/-0.684 mg x kg(-l) x day(-1), respectively). Our results show that the apo A-I(Zaragoza) variant results in heterozygosis in abnormal HDL particle composition and in enhanced catabolism of apo A-I and apo A-II without affecting significantly the secretion rates of these apolipoproteins and the LCAT activation.

Adult↗
PubMed2000

Co-morbidity in Gaucher's disease results of a nationwide enquiry in Spain.

SHORT INTRODUCTION: Gaucher's disease (GD) is an autosomal recessive disease produced by mutations of the Glucocerebrosidase gene. Carriers are considered to be healthy subjects because there is no manifestation of the disease, but they show signs of macrophage disfunction. The aim of the study was to determine if GD patients and non affected carriers risk suffering other diseases when compared to healthy non-carrier relatives. MATERIAL AND METHODS DESIGN: Epidemiologic study of historic cohorts. The fact that they have one or two mutated alleles has been considered to be the risk factor leading to other conditions (Dementia, Parkinson disease, Ischemic stroke, Ischemic heart disease, Non rheumatic valvular disease, Cancer hematological and non-hematological, Pulmonary fibrosis, Tuberculosis, Gallstones and Schizophrenia). All people, patients, carriers and healthy controls shared the same genetical background and environmental influence. - Patients and relatives enrolled on the Spanish Gaucher Disease Registry were evaluated. STATISTICS: For the Relative-Risk calculation the Mantel-Haenszel test was applied. Yates' correction was used when size sample was too small. A value of p <0.05 was accepted for statistical significance. RESULTS: 370 people, from 79 different families, were surveyed. We received evaluable information from 45 families (56%), totalling 258 people (69%): 59 healthy subjects (Mean age 32. 20, RANGE: 10-85; M 57.63%/F 42.37%), 132 carriers (Mean age 35.91, RANGE: 1-79; M 56.82%/F 43.18%) and 67 patients (Mean age 32.16, Range: 1-76; M 44.78%/F 55.22%. - Relative Risk of suffering any disease with regard to Gaucher's status: Patient vs Healthy 9.69 (95% Confidence interval [CI] 2.00-63.99; p 0.0006). Patient vs Carrier 3.74 (CI 1.53-9.27; p 0.001); Carrier vs Healthy 2.59 (CI 0. 52-12.50; p 0.21). Relative Risk of suffering any disease with regard to sex was 3.96 for female patients (CI 1.01-16.75; p 0.02) and 1.34 for female carriers (CI 0.27-6.75; p = 0.68). CONCLUSION: As a group, Gaucher's patients seem to have a greater risk of suffering other common unrelated diseases than carriers or healthy relatives. This excess of risk is particularly higher among female patients and can not be explained in terms of differences in age. Carrier status doesn't seem to highten the risk of suffering other diseases.

Adolescent↗
PubMed2000

Mutation analysis in 36 unrelated Spanish subjects with familial hypercholesterolemia: identification of 3 novel mutations in the LDL receptor gene.

We used the single strand conformation polymorphism (SSCP) method to investigate 36 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 receptor (LDLR) gene. Nineteen aberrant SSCP patterns were found, and the underlying mutations were characterized by DNA sequencing. In addition, we tested all patients for the presence of mutations in the gene coding for apolipoprotein B (apo B). Five missense mutations (Q71E, S156L, E256K, N543H and T705I), four nonsense mutations (W(-18)X, E10X, Q133X and C255X), six frameshift mutations (211delG, 518delG, 1045delC, 2085del19, 2207insT and 2393del9) and five splicing mutations (313+1G->C, 1061-8T->C, 1845+1G->C, 2140+5G->A and 2390-1G->C) were identified in the LDLR gene. In total, we detected 20 mutations, 3 of which, designated 1045delC, 1845+1G->C and 2207insT, have not been previously described. Seven patients were found to carry two different mutations in the same allele: W(-18)X and E256K (one patient), Q71E and 313+1G->C (two patients), 1061-8T->C and T705I (two patients), 518delG and 2140+5G->A (one patient) and N543H and 2393del9 (one patient). As we expected, there is a broad spectrum of mutations in the LDLR gene, given the genetic heterogeneity of the Spanish population.

Apolipoproteins B↗
PubMed1999

A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32.

Autosomal dominant hypercholesterolemia (ADH), one of the most frequent hereditary disorders, is characterized by an isolated elevation of LDL particles that leads to premature mortality from cardiovascular complications. It is generally assumed that mutations in the LDLR and APOB genes account for ADH. We identified one large French pedigree (HC2) and 12 additional white families with ADH in which we excluded linkage to the LDLR and APOB, implicating a new locus we named "FH3." A LOD score of 3.13 at a recombination fraction of 0 was obtained at markers D1S2892 and D1S2722. We localized the FH3 locus to a 9-cM interval at 1p34.1-p32. We tested four regional markers in another set of 12 ADH families. Positive LOD scores were obtained in three pedigrees, whereas linkage was excluded in the others. Heterogeneity tests indicated linkage to FH3 in approximately 27% of these non-LDLR/non-APOB ADH families and implied a fourth locus. Radiation hybrid mapping located four candidate genes at 1p34.1-p32, outside the critical region, showing no identity with FH3. Our results show that ADH is genetically more heterogeneous than conventionally accepted.

Adult↗
PubMed1999

Association of polymorphisms at the SR-BI gene locus with plasma lipid levels and body mass index in a white population.

The scavenger receptor class B type I (SR-BI) is a lipoprotein receptor that has been shown to be important in high density lipoprotein cholesterol (HDL-C) metabolism in mice. To determine its role in humans, we have characterized the human SR-BI gene and investigated its genetic variation in 489 white men and women. Five variants were demonstrated: 2 in introns (3 and 5) and 3 in exons (1, 8, and 11). Three variants at exons 1 and 8 and intron 5 with allele frequencies >0.1 were used to examine associations with lipid or anthropometric variables. The exon 1 variant was significantly (P<0.05) associated with increased HDL-C and lower low density lipoprotein cholesterol (LDL-C) values in men, but no associations were observed in women. The exon 8 variant was associated in women with lower LDL-C concentrations (3.05+/-0.98 mmol/L and 3.00+/-0.93 mmol/L for heterozygotes and homozygotes, respectively) compared with women homozygous for the common allele (3.39+/-1.09 mmol/L, P=0. 043). No associations for this variant were observed in men. Women carriers of the intron 5 variant showed a higher body mass index (23. 8+/-3.8 kg/m2, P=0.031) than those women homozygous for the common allele (22.4+/-3.4 kg/m2). Similar results were observed after haplotype analysis. Multiple regression analysis using HDL-C, LDL-C, and body mass index as dependent variables and age, sex, and each of the genetic variants as predictors also provided similar results. The associations found with both LDL-C and HDL-C suggest that SR-BI may play a role in the metabolism of both lipoprotein classes in humans.

Adult↗
PubMed1998

Beta-glucocerebrosidase gene locus as a link for Gaucher's disease and familial hypo-alpha-lipoproteinaemia.

BACKGROUND: Gaucher's disease is the most common lysosomal storage disorder, caused by deficiency of glucocerebrosidase resulting from homozygosity for any of several mutations of the glucocerebrosidase gene locus. Affected people have decreased concentrations of LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C). We assessed the association between mutations in the glucocerebrosidase locus and hypo-alpha-lipoproteinaemia. METHODS: We studied 258 people from 43 unrelated Spanish families. 57 participants were affected, 137 were non-affected carriers, and 64 were non-carriers. We determined glucocerebrosidase genotypes and measured plasmid lipids, apolipoproteins A-I, B, and E, and leucocyte glucocerebrosidase activity. FINDINGS: The most common glucocerebrosidase mutations were N370S (45%), L444P (23%), and G377S (5%). Deletions and recombinants accounted for another 5%, and point mutations in exons 5, 6, 9, and 10 were present in 12%. Affected participants had lower LDL-C and HDL-C concentrations than non-affected carriers (p<0.001) and non-carriers (p<0.001). HDL-C values were also significantly different between the non-affected carriers and non-carriers. Mutations at this locus may account for as much as 19.5% of the genetic variability in HDL-C in the population studied. INTERPRETATION: Heterozygosity for these mutations at the glucocerebrosidase locus does not result in clinical expression of Gaucher's disease but can decrease HDL-C concentrations. Given the high frequency of these mutations, the glucocerebrosidase locus might lead to familial low alpha-lipoproteinaemia in up to 2% of the general population and be one of the most common known genetic causes of HDL-C.

Adult↗
PubMed1998

LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis.

Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia (FH), a common autosomal dominant disorder. The LDLR database is a computerized tool that has been developed to provide tools to analyse the numerous mutations that have been identified in the LDLR gene. The second version of the LDLR database contains 140 new entries and the software has been modified to accommodate four new routines. The analysis of the updated data (350 mutations) gives the following informations: (i) 63% of the mutations are missense, and only 20% occur in CpG dinucleotides; (ii) although the mutations are widely distributed throughout the gene, there is an excess of mutations in exons 4 and 9, and a deficit in exons 13 and 15; (iii) the analysis of the distribution of mutations located within the ligand-binding domain shows that 74% of the mutations in this domain affect a conserved amino-acid, and that they are mostly confined in the C-terminal region of the repeats. Conversely, the same analysis in the EGF-like domain shows that 64% of the mutations in this domain affect a non-conserved amino-acid, and, that they are mostly confined in the N-terminal half of the repeats. The database is now accessible on the World Wide Web at http://www.umd.necker.fr

Computer Communication Networks↗
PubMed1998

Human apolipoprotein A-I gene promoter mutation influences plasma low density lipoprotein cholesterol response to dietary fat saturation.

Previous studies have shown that the A to G transition occurring at position -75 bp upstream of the transcriptional start site in the human apolipoprotein A-I gene may affect plasma high density lipoprotein cholesterol (HDL-C) levels and low density lipoprotein cholesterol (LDL-C) response to changes in amount of dietary fat. We have examined the response to dietary fat saturation as a function of this mutation in 50 men and women. Subjects were first fed a saturated (SAT) fat diet (35% fat, 17% SAT) for 28 days, followed by a diet rich in monounsaturated fatty (MUFA) acids (35% fat, 22% MUFA) for 35 days and a diet rich in polyunsaturated (PUFA) fat (35% fat, 13% PUFA) for 35 days. All meals were prepared and consumed at the study sites. Lipoproteins were measured at the end of each diet period. The allele frequency for the A allele was 0.13. Subjects carrying the A allele had higher plasma cholesterol, LDL-C and triglyceride levels than those homozygotes for the G allele. As compared to the SAT diet, a PUFA diet induced significantly greater plasma total (P = 0.003) and LDL-C decreases (P = 0.001) in G/A women (-1.62 and -1.32 mmol/l, respectively) than in G/G subjects (-0.87 and -0.74 mmol/l for plasma and LDL-C, respectively). Multiple regression analysis demonstrated that in women, the variability in LDL-C response from a diet rich in SAT fat to a diet rich in PUFA was primarily due to LDL-C levels (during the SAT phase), accounting for 55.1% of the variance, waist to hip ratio (W/H; 11.4%) and the G/A polymorphism (10%). Whereas in men the major determinant of this response was smoking (21.4%). In conclusion, the G/A polymorphism appears to have a small but significant effect on plasma LDL-C responsiveness to changes in dietary fat saturation specially in women.

Adult↗
PubMed1998

Lipoprotein(a) and the significance of the association between platelet glycoprotein IIIa polymorphisms and the risk of premature myocardial infarction.

Platelet glycoprotein IIb/IIIa may be involved in the pathogenesis of myocardial infarction as the key element in platelet aggregation and as the binding site of lipoprotein(a) to platelets, inhibiting plasminogen binding and activation. Recently, a strong association between the P1A2 polymorphism of the glycoprotein IIIa gene and acute coronary thrombosis has been reported. although this has not been confirmed. In an associated study, we determined plasma lipoprotein levels, the apo E genotype and the P1A genotype in 250 males under 55 years with myocardial infarction and they were compared with 250 age- and sex-matched controls. Patients showed an over-representation of the epsilon3/4 genotype with respect to the control group. We found that there were no differences in the allelic frequency of P1A2 between case patients and age-matched controls (chi2 = 0.05, P = 0.92) and that subjects bearing the P1A2 allele showed higher plasma lipoprotein(a) concentration than p1A1/P1A1 individuals. Therefore, in this population there is no association between carriage of p1A2 allele and increased risk of myocardial infarction but the carriage of P1A2 is associated with higher plasma Lp(a) concentration.

Adult↗
PubMed1998

Polymorphism of the platelet glycoprotein IIIa gene in patients with coronary stenosis.

Based on genetic variability, structural differences in the glycoprotein IIb/IIIa platelet receptor for adhesive proteins result in individual differences in the thrombogenicity of platelets. Recent studies suggest a controversial association between a genetic polymorphism of the glycoprotein IIIa gene (PlA2) and the risk of coronary artery disease. In our study, the prevalence of the PlA2 allele in a group of patients undergoing percutaneous coronary revascularization was 37%, a value significantly higher than in controls [13%, odds ratio (OR) = 3.93, 95% CI, 1.84 to 8.53] suggesting a significant association between this polymorphism and documented coronary stenosis, which is strongest among <60 years old patients (OR = 12.30, 95% CI, 2.98 to 70.93). This polymorphism represents an inherited risk factor for severe cardiovascular disease due to coronary occlusion.

Aged↗
PubMed1997

[Clinical characteristics of type I Gaucher's disease in Spain. Preliminary results of national survey. Spanish Group on Gaucher's Disease].

BACKGROUND: To know the incidence and distribution of Gauchers's disease (GD) in Spain, a national inquiry was carried out in order to analyze the clinical, genetic and evolutive features of these patients. PATIENTS AND METHODS: A questionnaire including demographic, clinical, diagnostic, biological, radiological and evolutive data was sent to the hospitals. Each case with a presumptive diagnosis was considered a "censored patient". The cases without enzymatic or genetic diagnosis were studied in a reference laboratory (the same for all the samples). The Zimran's Severity index was employed to evaluate the clinical status. The enzymatic activity of acid beta-glucosidase was studied in cellular extracts of peripheral blood granulocytes by a fluorescent method using an artificial substrate (methyl-umbeliferyl-beta-deglycoside). The characterization of the mutations of the glucosidase gene was determined by PCR molecular analysis in the samples of DNA studying the mutations: N370S, L444P, 84GG and IVS2+1. RESULTS: Seventy five patients were censored; in 48 the inquiry was completed. These patients belonged to 54 families. The mean age at diagnosis was 24.7 years, being the M/F distribution 16/32. The illness was asymptomatic in 13.3%, visceral disease was present in 83.3% of patients and bone disease in 70.8%. The 45.8% of patients had hemoglobin levels < 110 g/l, 35.4% low leucocyte count < 4,0 x 10(9)/l and 77.0% low platelet count < 150 x 10(9)/l. High acid phosphatase levels were observed in 100% of cases and in 34.7% biochemical hepatic dysfunction was observed. The test for acid glucosidase showed a marked decrease in enzymatic activity. In 71% of the patients morphologic documentation (splenic or hepatic tissue, bone marrow biopsy or aspirates) was performed. The most frequent mutations observed were N370S (47.7% of the alleles detected), and L444P (24.4%). In 18.7% of the cases the disease was stable or slightly progressive, in 27.0% the spleen was removed between 1-14 years of the being made and 45.8% were put onto an alglucerase trial. CONCLUSIONS: The incidence of GD in Spain is at present lower that the previously reported for other european countries. The clinical features are not different except in the case of bone disease, less frequent in our cases, probably limited by the absence of MR. The pattern of distribution of mutation is also similar.

Adult↗
PubMed1996

Incomplete dominance of type III hyperlipoproteinemia is associated with the rare apolipoprotein E2 (Arg136-->Ser) variant in multigenerational pedigree studies.

In the process of screening apolipoprotein (apo) E genotypes in a population of subjects with lipid abnormalities, we have identified five subjects (one homozygote and four heterozygotes) with an abnormal 109 base pairs band following apo E restriction isotyping of amplified DNA with the restriction endonuclease CfoI. The polymerase chain reaction (PCR) products were cloned and their sequencing revealed a C-->A substitution at the first nucleotide of codon 136. This mutation resulted in an amino acid substitution Arg to Ser, previously described as apo E2 Christchurch. Family studies were carried out for four of the probands. In these kindreds, stepwise multiple regression analyses indicated that 78% of the cholesterol variability in men was predicted by body mass index, age and the rare apo E2 (Arg136-->Ser) variant. In women, age and the apo E2 (Arg136-->Ser variant predicted 54.9% of the variability in cholesterol levels. Linkage analysis suggested that the presence of the apo E2 (Arg136-->Ser) variant was linked with the occurrence of cholesterol enriched triglyceride rich lipoproteins and with an incomplete dominance of type III hyperlipoproteinemia. Our data indicates that this mutation may be a relatively common cause of dyslipidemia in the Spanish population.

Adult↗
PubMed1993

Adenine for guanine substitution -78 base pairs 5' to the apolipoprotein (APO) A-I gene: relation with high density lipoprotein cholesterol and APO A-I concentrations.

A common mutation, adenine (A) for guanidine (G) substitution (G/A) has been located -78 bp 5' to the apo A-I gene. This region has been shown to be involved in the transcriptional regulation of the apo A-I gene. Previous studies have shown that this mutation is associated with altered high density lipoprotein cholesterol (HDL-C) levels, although these findings have not been consistent. We have studied the frequency of this mutation in 125 subjects (60 males and 65 females) selected because they had HDL-C levels below the 25th (low HDL) or above the 75th (high HDL) percentile of the population distribution. The presence of the mutation was detected by Msp I digestion of a 259 bp fragment of PCR amplified DNA. The allele frequency was similar in both groups (0.20 for the lowest HDL group and 0.28 for the highest HDL group, p > 0.05), although a non-significant trend was observed in a higher frequency of the A/A genotype in the highest HDL females (17.5%) vs only 6.7% in the lowest HDL female group. In conclusion, in this population the G/A mutation was not significantly associated with HDL-C or apo A-I plasma levels.

Adult↗