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Biomedical subjects

S Bertolini

Publications and source records attributed to S Bertolini.

At least 37 records · Page 2Linked to original sources
PubMed2000

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

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 (+18%) and high density lipoprotein cholesterol lower (-5%) 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 >30 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 receptor-defective subjects. Wide interindividual variability in LDL cholesterol levels was found in each cluster. Apolipoprotein E genotype analysis showed a lowering effect of the epsilon2 allele and a raising effect of the epsilon4 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.

Adult↗
PubMed2000

Characterization and screening of a point mutation in LDL receptor gene found in southern Italy (FHAvellino).

The finding that the missense mutation C331W in the exon 7 of LDL-receptor gene, previously reported to occur in Holland and Belgium, caused the homozygote familial hypercholesterolemia (FH) in an individual from the district of Avellino induced us to search the mutation in a large area of region Campania. This was made with simple screening methods developed by ourselves and based on either the recognition of a primer-induced Fok I restriction site in the mutant allele or the PCR allele-specific amplification (PASA) of mutant allele. They were applied to a total of 144 unrelated cases recruited from where the mutation was more likely to occur. We failed to reveal any new case of C331W mutation that is indeed not common within the area of this screening, at spite of having been found in different countries.

Adult↗
PubMed1999

GH, IGFBP-1, and IGFBP-3 response to oral glucose tolerance test in perimenopausal women: no influence of body mass index.

OBJECTIVES: an increasing interest is being focused on the role of the somatotropic axis in the modulation of body weight and fat distribution, particularly in climacteric women. The influence of the glycometabolic state on the somatotropic axis in postmenopausal and in obese subjects has not been investigated. The aim of the present study is to evaluate whether menopause and body mass index (BMI) affect the response of growth hormone (GH), insulin-like growth factor-binding protein-1 (IGFBP-1) and -3 (IGFBP-3) to the oral glucose tolerance test (OGTT). METHODS: the study included 24 women, aged 45-55 years, categorized into 4 groups, premenopausal pre-obese (BMI = 28.5 +/- 0.8 Kg/m2) and normal body weight (BMI = 22.2 +/-1.1 Kg/m2), and postmenopausal pre-obese and normal body weight. All women underwent: (1) a biophysical evaluation with determination of waist/hip ratio; (2) an assessment of fat and lean tissue mass and body fat distribution by total body DEXA; and to (3) an OGTT. RESULTS: in response to OGTT plasma GH levels significantly decreased in all groups, but the relative decrease was more prominent in the lean subjects. A significant decrease of IGFBP-1 levels in response to OGTT was observed in all women, regardless of menopausal age and BMI, while IGFBP-3 levels did not significantly change in either group. CONCLUSIONS: in conclusion, the impact of both BMI and menopausal condition on GH, IGFBP-1, and -3 response to OGTT is limited to a blunted GH response in overweight women compared with normally-weighing ones. These findings appear to rule out the hypothesis that a common glycometabolic derangement may affect both the modifications of body weight and of the somatotropic axis observed in perimenopausal women.

Body Composition↗
PubMed1999

Apolipoprotein E and alpha-1-antichymotrypsin allele polymorphism in sporadic and familial Alzheimer's disease.

Alzheimer disease (AD) patients with both sporadic and familial forms of AD and non-demented controls were genotyped for common polymorphisms in the signal peptide for alpha-1-antichymotrypsin (ACT) gene and in two different regions of apolipoprotein E (APOE) gene. The ACT TT genotype was over-represented (P = 0.025) in patients with early onset of sporadic AD. In this patient's group ACT TT genotype conferred a significant crude odds ratio for the disease (OR = 2.09; 95% CI = 1.09-4.00, P = 0.025). After adjustment for the APOE epsilon4 and APOE -491 genotypes, logistic regression analysis confirmed that the ACT TT genotype resulted independently associated with early onset AD (adjusted OR = 2.56; 85% CI = 1.3-5.2, P = 0.009). The frequency of APOE epsilon4 allele was increased in AD, as expected (OR = 5.92, 95% CI = 3.60-9.70, P = 0.0001). On the contrary, the APOE -491 A/T genotypes were not associated with AD. No preferential association of the APOE epsilon4 allele or APOE -491 A/T genotypes with ACT A/T alleles was observed in AD. Present findings indicated that subjects with ACT TT genotype had an increased risk of developing AD and suggested that this genotype influenced the risk of an early onset of the disease by affecting the production of ACT molecules.

Aged↗
PubMed1999

Rapid screening of the LDL receptor point mutation FH-Genoa/Palermo. Mutation in brief no. 238. Online.

The LDL-receptor gene point mutation FH-Genoa/Palermo is the most frequent mutation responsible for Familial Hypercholesterolemia in Sicily. The mutation does not introduce or abolish any useful restriction site. We establish a GeneComb-based strategy to identify this mutation in a population of Sicilian unrelated clinically diagnosed FH probands. The method was very sensitive and specific; 12 out of 90 (13.3%) unrelated FH probands were found to carry the FH-Genoa/Palermo mutation. According to these results, the FH-Genoa/Palermo is the more frequent LDL-receptor gene mutation among the Sicilian FH patients. Moreover FH-Genoa/Palermo is the mutation cluster to date more represented in Southern Italy.

Genetic Testing↗
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

Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans.

Mitochondrial DNA (mtDNA) is characterized by high variability, maternal inheritance, and absence of recombination. Studies of human populations have revealed ancestral associated polymorphisms whose combination defines groups of mtDNA types (haplogroups) that are currently used to reconstruct human evolution lineages. We used such inherited mtDNA markers to compare mtDNA population pools between a sample of individuals selected for successful aging and longevity (212 subjects older than 100 years and in good clinical condition) and a sample of 275 younger individuals (median age 38 years) carefully matched as to sex and geographic origin (northern and southern Italy). All nine haplogroups that are typical of Europeans were found in both samples, but male centenarians emerged in northern Italy as a particular sample: 1) mtDNA haplogroup frequency distribution was different between centenarians and younger individuals (P=0.017 by permutation tests); and 2) the frequency of the J haplogroup was notably higher in centenarians than in younger individuals (P=0.0052 by Fisher exact test). Since haplogroups are defined on the basis of inherited variants, these data show that mtDNA inherited variability could play a role in successful aging and longevity.

Adult↗
PubMed1999

Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia.

The aim of this study was the characterization of mutations of the LDL receptor gene in 39 Italian patients with homozygous familial hypercholesterolemia, who were examined during the period 1994 to 1996. The age of the patients ranged from 1 to 64 years; one third of them were older than 30. Plasma LDL cholesterol level ranged from 10.8 to 25.1 mmol/L. The residual LDL receptor activity, measured in cultured fibroblasts of 32 patients, varied from <2% to 30% of normal and was inversely correlated with the plasma LDL cholesterol level (r=-0.665; P<0.003). The most severe coronary atherosclerosis was observed in those patients with the lowest residual LDL receptor activity (</=5% of normal) and the highest plasma LDL cholesterol levels. Twenty-nine patients (23 of whom were unrelated) were found to be homozygotes at the LDL receptor locus. In this group we discovered 2 major rearrangements and 12 different point mutations (9 in the coding region and 3 in splice sites). Some mutations (D200G, C358R, V502M, G528D, and P664L) were found in 3 or more unrelated patients. Patients with the same mutation shared the same haplotype at the LDL receptor gene locus and came from the same geographic area. Ten patients (9 of whom were unrelated) were found to be compound heterozygotes. The mutations found in this group consisted of one large deletion and 12 point mutations (11 in the coding sequence and one in a splice site). In 3 compound heterozygotes we failed to identify the second mutant allele at the LDL receptor locus. These observations confirm the allelic heterogeneity underlying familial hypercholesterolemia in the Italian population and indicate that the variability of phenotypic expression of homozygous familial hypercholesterolemia is, to a large extent, related to the type of mutation of the LDL receptor gene.

Adolescent↗
PubMed1999

[Familial hypercholesterolemia and mutations of the gene for low-density lipoproteins in Italy].

The review takes into account molecular bases and major implications for public health in our country of familial hypercholesterolemia (FH) caused by mutations in LDL receptor (LDLR) gene. The relevance of the problem is evidenced by the fact that (a) about 120,000 Italians affected by heterozygous FH face a cardiovascular risk much higher than normal individuals, and (b) their identification is difficult because of the plethora of mutations existing in the country. This report deepens also the relationships between alterations in the coding sequence of LDLR gene and in the function of LDLR protein. Furthermore, it describes, in terms of molecular characteristics and diffusion, the 42 mutations so far detected in Italy that cause about 30% of FH cases. This led us to hypothesize the existence in our country of over hundred different mutations present within defined geographical areas where, in a few cases, they may also have a relatively high incidence (i.e., the so-called FH-clusters). Finally, preliminary studies mentioned here point out the existence of significant correlations between phenotype and genotype of FH and suggest the possibility of realizing on a large scale an early diagnosis and therapy of pathologies caused by a function deficit in LDL receptor.

Heterozygote↗
PubMed1998

A nonsense mutation (R242X) in the branched-chain alpha-keto acid dehydrogenase E1alpha subunit gene (BCKDHA) as a cause of maple syrup urine disease. Mutations in brief no. 160. Online.

Mutation analysis of DNA from cultured amniocytes with absent branched-chain alpha-ketoacid dehydrogenase activity revealed a C to T transition producing a nonsense mutation (R242X) in exon 7 of the gene encoding the E1a subunit of this multienzme complex (BCKDHA). This pregnancy occured in a large consanguinous pedigree with mutiple individuals with maple syrup urine disease (MSUD). PCR amplification of the region surrounding exon 7 allowed the identification of this mutation as well as two other previously identified mutations which cause MSUD.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1998

Somatotropic axis and body weight in pre-menopausal and post-menopausal women: evidence for a neuroendocrine derangement, in absence of changes of insulin-like growth factor binding protein concentrations.

The altered function of the somatotropic axis observed in perimenopause may underlie the changes in body weight and fat distribution. The aim of the present study was to evaluate, in pre-menopausal and post-menopausal women with body mass index (BMI) > or = or <25, the basal plasma levels of growth hormone (GH), insulin-like growth factor (IGF)-I and -II, IGF binding protein (IGFBP)-1 and -3, and the response of GH and IGFBP-1 and -3 to GH releasing hormone (GHRH) and GHRH plus arginine tests. GH and IGF-I basal concentrations were significantly higher in pre-menopausal than in post-menopausal women, while IGF-II, IGFBP-1 and IGFBP-3 concentrations did not vary significantly. IGFBP-1, but not IGFBP-3, concentrations were higher in lean than in obese patients. Insulin concentrations were significantly higher in obese patients, while no differences were observed between pre-menopausal and post-menopausal women. In all subjects, GH concentrations increased significantly during GHRH test; pre-menopausal and lean women showed a higher response compared to post-menopausal and obese women. The GHRH plus arginine test stimulated GH response in all women, irrespective of age and BMI. IGFBP-1 and -3 concentrations did not vary in response to GHRH or GHRH plus arginine tests. The somatotropic axis undergoes modifications in post-menopausal women, apparently not involving IGFBP-1 and -3. Arginine infusion restores the response of GH to GHRH, in both post-menopausal and obese subjects. A somatostatinergic hyperactivity at the climateric period may underlie the changes both in body weight and somatotropic axis.

Arginine↗
PubMed1998

A 'de novo' point mutation of the low-density lipoprotein receptor gene in an Italian subject with primary hypercholesterolemia.

Severe hypercholesterolemia was found in an 11-year-old boy with no family history of familial hypercholesterolemia. The reduced LDL-receptor activity in cultured skin fibroblasts (40% 125I-LDL degradation as compared with a control cell line) indicated the presence of an LDL-receptor defect. The analysis of the promoter region and the exons of LDL-receptor gene by single strand conformation polymorphism revealed an abnormal migration pattern in exon 1, which was due to a T --> A transversion at nucleotide 28 of the cDNA. This novel mutation causes an arginine for tryptophane substitution at position - 12 of the signal peptide (W-12R) and introduces an AviII restriction site in exon 1. Screening of the mutation by polymerase chain reaction (PCR) amplification of exon 1 and AviII digestion revealed that none of the proband's family members carried the mutation. Non-paternity was excluded after the analysis of a battery of 14 short tandem repeats located in 13 different chromosomes. These results are consistent with the hypothesis that the proband is heterozygous for a 'de novo' mutation of the LDL-receptor gene producing a non-conservative amino acid substitution. We suggest that the change in the net charge of the signal peptide, caused by the addition of a positively charged amino acid, impairs the co-translational translocation of the nascent receptor protein across the endoplasmic reticulum membrane.

Adolescent↗
PubMed1998

Double-Blind Comparison of Apolipoprotein and Lipoprotein Particle Lowering Effects of Atorvastatin and Pravastatin Monotherapy in Patients With Primary Hypercholesterolemia.

METHODS AND RESULTS: A total of 305 subjects with primary hypercholesterolemia were randomized in a 3:1 ratio to receive either atorvastatin 10 mg daily or pravastatin 20 mg daily according to a 16-week double-blind comparative study of the effect on apolipoprotein and lipoprotein particle levels. All patients had low-density lipoprotein (LDL)-cholesterol levels between 4.2 and 6.6 mM and triglyceride concentrations below 4.5 mM at baseline. After 16 weeks of treatment, apoB (-27% and -16%; P <.001), apoE (-13.3% and -5.6%; P <.05) and the triglyceride-rich LpC-III:B particle (-33% and -26%; P <.05) levels were reduced to a significantly greater extent in the atorvastatin than in the pravastatin treatment group. Both atorvastatin and pravastatin increased apoA-I levels, an effect that was more pronounced in the pravastatin group (+7% and +11%; P <.002). The increased apoA-I levels predominated on LpA-I in the atorvastatin group (+11%) and on LpA-I:A-II in the pravastatin group (+13%). ApoA-II levels were decreased with atorvastatin to a greater extent than with pravastatin (-1% and +2.8%; P <.05). CONCLUSIONS: Although atorvastatin and pravastatin belong to the same therapeutic family, they produce different effects in apoliprotein concentrations in hypercholesterolemic patients. Atorvastatin, an agent of the new generation, appears to efficiently reduce apoB-containing lipoprotein particles containing apoC-III.

Journal Article↗
PubMed1998

Two novel mutations consisting in minor gene rearrangements in the human low density lipoprotein receptor gene in Italian patients affected by familial hypercholesterolemia. Mutations in brief no. 194. Online.

Mutations in the low density lipoprotein (LDL)-receptor gene cause familial hypercholesterolemia (FH), an autosomal dominant disease associated to an increased risk of premature atherosclerosis. We describe two novel mutations found in Italian families and consisting in minor gene rearrangements. The first one (FH-Pisa) is a tetranucleotide insertion occurring in exon 8, which causes a frameshift and a premature stop codon. The second one (FH-Chieti3) occurs at the 3'-end of exon 4 and consists in a trinucleotide deletion replaced by a six-base insertion, so that the reading frame is maintained with a glutamic acid-to-cysteine substitution at codon 207 and the insertion of a lysine at codon 208. Both mutations occur in regions of the LDL-receptor gene which can be considered hotspots for minor rearrangements.

Amino Acid Substitution↗
PubMed1998

Simple detection of a point mutation in LDL receptor gene causing familial hypercholesterolemia in southern Italy by allele-specific polymerase chain reaction.

Polymerase chain reaction (PCR) amplification of specific alleles allowed the rapid detection of a point mutation (missense Gly528 --> Asp) in exon 11 of the low density lipoprotein receptor gene which was otherwise not detectable by exon amplification and enzymatic digestion as it does not modify the normal restriction pattern. The mutant allele, designated as FH-Palermo-1 from the origin of the first carrier family identified, gave a specific PCR product of 109 bp clearly distinct from the product of 168 bp obtained from other alleles with a nonspecific couple of primers. This method allowed us to distinguish one positive sample mixed with up to 11 parts of normal DNA. Furthermore, the specific amplification product was characterized by a Bsm I restriction site not present in nonspecific products.

Alleles↗