PubMed Health⌕ Search

Biomedical subjects

P Izzo

Publications and source records attributed to P Izzo.

At least 19 recordsLinked to original sources
PubMed2004

The adiponectin gene SNP+45 is associated with coronary artery disease in Type 2 (non-insulin-dependent) diabetes mellitus.

BACKGROUND: The ACRP30/adiponectin gene on chromosome 3q27, a region linked to the metabolic syndrome, encodes for the abundant adipocyte-specific secreted protein. Consistent rodent and human studies suggested that this adipokine may be a molecular link between metabolic and cardiovascular diseases. AIMS: In order to investigate the role of single nucleotide polymorphisms (SNPs) within the APM1 gene in the susceptibility to coronary artery disease (CAD), we performed a case-control study on Caucasian Type 2 (non-insulin-dependent) diabetic patients, a population at high-risk for CAD. METHODS: Five APM1 SNPs were genotyped in 162 Type 2 diabetic French and Swiss subjects with CAD and in 315 Type 2 diabetic French and Swiss subjects without CAD. RESULTS: In univariate analysis, SNP+45 T>G was associated with CAD (OR 1.9 95% CI 1.2-2.9 P = 0.0036). In multivariate analysis, SNP+45 T>G remained associated with CAD (OR 1.2 95% CI 0.8-1.9 P = 0.017), independently of classical cardiovascular risk factors including components of the metabolic syndrome. SNP haplotype analyses revealed a CAD protective combination of all SNP wild-type alleles (OR 0.5 95% CI 0.3-0.7 P = 0.0006). CONCLUSIONS: Our study, performed in diabetic subjects, revealed an association between individual SNP+45 in the APM1 gene and CAD. Furthermore, the susceptibility for CAD due to SNP+45 was independent of classic cardiovascular risk factors. Further studies will be necessary to confirm the role of SNP+45 in the development of CAD. However, ACRP30/adiponectin may contribute to atherosclerosis susceptibility in high-risk populations such as Type 2 diabetic subjects.

Adiponectin↗
PubMed2003

A novel zinc finger transcriptional repressor, ZNF224, interacts with the negative regulatory element (AldA-NRE) and inhibits gene expression.

The interaction between the negative cis-element (AldA-NRE) and p97 repressor nuclear protein is a key step in modulating transcription of the human and mouse aldolase A (AldA) gene during the cell cycle and differentiation. In an attempt to clarify the role of transcriptional repression in regulating gene expression, we purified, from HeLa cells, the nuclear protein that specifically binds to the AldA negative regulatory element (NRE). Matrix-assisted laser desorption ionization-time of flight analysis and examination of protein profiles from the SwissProt database revealed that the previously defined p97 repressor is ZNF224, a zinc finger protein. We demonstrate that ZNF224, a Kruppel-like zinc finger transcription factor, is the repressor protein that specifically binds to the negative cis-element AldA-NRE and affects the AldA-NRE-mediated transcription.

Amino Acid Sequence↗
PubMed2001

Phenotype-genotype correlations in an extended family with adenomatosis coli and an unusual APC gene mutation.

PURPOSE: Genotype-phenotype correlations in familial adenomatous polyposis are only partially understood and, in particular, little is known about the biomolecular characteristics of desmoid tumors, which are one of the most serious and frequent manifestations of familial adenomatous polyposis. In the present study, we describe a family with familial adenomatous polyposis, with peculiar clinical characteristics (i.e., frequency and severity of desmoid neoplasms) associated with an unusual mutation of the adenomatosis polyposis coli gene. If confirmed by other investigations, these findings might help to understand the biologic mechanisms by which specific adenomatosis polyposis coli mutations predispose to desmoid tumors. METHODS: The family with familial adenomatous polyposis, living in southern Italy, was studied from 1985 to the end of 1999; at this date, 15 individuals have been affected by histologically verified familial adenomatous polyposis, 11 of whom had desmoid tumors. A total of 19 family members were studied for adenomatosis polyposis coli gene mutations; 13 of them tested positive and 6 negative. The analytical procedure-previously described-consisted of the extraction of peripheral blood cell DNA, amplification of exon 15 by polymerase chain reaction, single-strand conformation polymorphism analysis, and direct sequencing of the DNA fragment containing the mutation. RESULTS: The main clinical features of the family were 1) a high frequency of desmoid tumors and, consequently, a high penetrance of the desmoid trait in all branches of the family and in 11 (73.3 percent) of 15 affected individuals and 2) severity of desmoids in at least 4 family members, 2 of whom died for causes related to the presence of these tumors. The molecular basis of the disease was an uncommon mutation of the adenomatosis polyposis coli gene, consisting of a large deletion of 310 base pairs at codon 1,464, with duplication of the breakpoint (4,394ins15del310), leading to a stop codon at position 1,575. CONCLUSIONS: The present study shows that a truncating mutation in the adenomatosis polyposis coli gene at the beginning of the region frequently associated with desmoids induced a familial adenomatous polyposis phenotype featured by a high penetrance of the desmoid trait, with severe disease in several affected members of both sexes. The study may help to understand the biologic mechanisms of genotype-phenotype correlations in adenomatosis coli.

Adenomatous Polyposis Coli↗
PubMed2001

[Peutz-Jeghers syndrome: case report and update on diagnosis and treatment].

Peutz-Jeghers syndrome is a rare autosomal dominantly inherited condition with an incidence of 1/120.000 liveborns, characterized by the presence of hamartomatous gastrointestinal polyps and mucocutaneous pigmentation. This syndrome predisposes to various clinical problems such as intussusception and cancer development in different loci (gastrointestinal tract, breast and ovary). For this reason, PJS patients should undergo a surveillance protocol of the genital and gastrointestinal apparatus. Therefore, the early diagnosis of PJS in at-risk family members is very important in preventing cancer development. Germline mutations within the LKB1 or Serine Threonine Kinase (STK11) gene, located on chromosome 19p13.3, are responsible for most cases of PJS so far studied. The existence of a second locus is suspected on chromosome 19q13.4 in a minority of families. The LKB1 gene, recently cloned, encodes the Serine Threonine Kinase LKB1 and is ubiquitously expressed. The identification of the disease-causing mutation in each family makes it possible to perform a presymptomatic diagnosis; therefore, only the mutation carriers will undergo the clinical surveillance program. In this paper, the case of a PJS patient who has been surgically treated is presented. The DNA screening of the LKB1 gene in this patient has led to the identification of the causing mutation. A critical review of the literature and is also presented as well as the proposal to establish an Italian Registry of PJS.

Adult↗
PubMed2000

Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.

Turcot's syndrome is a genetic disease characterized by the concurrence of primary brain tumors and colon cancers and/or multiple colorectal adenomas. We report a Turcot family with no parental consanguinity, in which two affected sisters, with no history of tumors in their parents, died of a brain tumor and of a colorectal tumor, respectively, at a very early age. The proband had a severe microsatellite instability (MIN) phenotype in both tumor and normal colon mucosa, and mutations in the TGFbeta-RII and APC genes in the colorectal tumor. We identified two germline mutations within the PMS2 gene: a G deletion (1221delG) in exon 11 and a four-base-pair deletion (2361delCTTC) in exon 14, both of which were inherited from the patient's unaffected parents. These results represent the first evidence that two germline frameshift mutations in PMS2, an MMR gene which is only rarely involved in HNPCC, are not pathogenic per se, but become so when occurring together in a compound heterozygote. The compound heterozygosity for two mutations in the PMS2 gene has implications for the role of protein PMS2 in the mismatch repair mechanism, as well as for the presymptomatic molecular diagnosis of at-risk family members. Furthermore, our data support and enlarge the notion that high DNA instability in normal tissues might trigger the development of cancer in this syndrome.

Adenoma↗
PubMed1999

PKC-dependent phosphorylation of the p97 repressor regulates the transcription of aldolase A L-type promoter.

Expression of mouse aldolase A L-type mRNA is negatively modulated by a cis element (AldA-NRE), located within the aldolase A distal promoter (pL). AldA-NRE interacts with a 97-kDa repressor protein (p97), which binds DNA in a cell cycle-dependent manner. We demonstrate that the binding between AldA-NRE and p97 decreases during differentiation of human Caco-2 cells and is inversely correlated with L-type mRNA expression. Phosphorylation of the p97 repressor weakened its DNA binding activity in differentiated Caco-2 cells, while dephosphorylation enhanced the binding in proliferating cells. Stimulation of protein kinase C (PKC) in vivo decreased the binding of p97 to AldA-NRE and stimulated transcription, while inhibition of PKC stimulated p97 binding and downregulated transcription. These findings suggest that PKC is a mediator of the binding and silencing function of the p97/AldA-NRE repressor complex.

3T3 Cells↗
PubMed1999

Mutation analysis of the BRCA1 and BRCA2 genes results in the identification of novel and recurrent mutations in 6/16 flemish families with breast and/or ovarian cancer but not in 12 sporadic patients with early-onset disease. Mutations in brief no. 224. Online.

Since the identification of the BRCA1 and BRCA2 genes (MIM#s 113705 and 600185), more than hundred different mutations throughout both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. We analyzed 12 sporadic female patients with breast cancer before age 35, as well as 16 unrelated families, presenting with either (i) at least 3 first degree relatives with breast and/or ovarian cancer diagnosed at any age, or (ii) at least 2 first and/or second degree relatives with breast and/or ovarian cancer before age 45 years. We performed a protein truncation test for BRCA1 exon 11 and BRCA2 exons 10 and 11 and heteroduplex analysis for all the remaining exons of BRCA1 and 2. Presence of genomic deletions encompassing exons 13 or 22 of BRCA1, known to be Dutch founder mutations, was investigated by PCR. In 6/16 (37.5%) unrelated families the causal mutation in either the BRCA1 or BRCA2 gene was identified. Four different mutations were found in the BRCA1 gene: IVS5+3A>G (intron 5), 1191delC (exon 11), R1443X (exon 13), IVS22+5G>A (intron 22) and two in the BRCA2 gene: 6503delTT (exon 11), 6831delTG (exon 11). 1191delC (BRCA1) and 6831delTG (BRCA2) are novel mutations. IVS5+3A>G in exon 5 of BRCA1 published by Peelen et al. (1997) as a novel Belgian mutation, was identified in one additional family, not fulfilling our inclusion criteria. In the group of 12 sporadic female patients no mutations were found.

Adult↗
PubMed1999

Three submicroscopic deletions at the APC locus and their rapid detection by quantitative-PCR analysis.

We describe three unrelated kindreds, affected by familial adenomatous polyposis (FAP), with 5q submicroscopic deletions that encompass the entire adenomatous polyposis coli (APC) gene and the adjacent DP1 gene. In one family the deletion encompasses also the MCC (mutated in colon cancer) gene. Affected members of these families had dysplastic adenomatous polyps and congenital hypertrophy of the retinal pigment epithelium (CHRPE); no individual was affected by mental retardation or facial dysmorphism. The deletions were detected by linkage analysis with several intragenic and closely flanking polymorphic markers and confirmed by a quantitative PCR analysis. This procedure could have an impact on the detection of the molecular defect in FAP patients in whom mutational analysis fails to identify the specific mutation.

Adenomatous Polyposis Coli↗
PubMed1999

[The intracystic concentration of MCA in the fluid from large breast cysts].

75 patients with breast gross cystic disease and no cancer have been included in the study. For each patients serous and intracystic concentrations of MCA have been measured. The aim of the study is to assess whether if a relation between intracystic concentration of the marker and resistance and capability of cellular reproduction exists (confirmed by the release of the cyst). The analysis of intracystic values shows that synthesis of MCA is an intrinsic peculiarity of cytologic kind. It is apparently independent from inflammatory or hemorrhagic contemporary processes.

Adult↗
PubMed1999

Erythrocytes stored in CPD SAG-mannitol: evaluation of their deformability.

The erythrocytes deformability of three blood samples coming from healthy donors has been evaluated by Laser-assisted Optical Rotational Cell Analyzer (LORCA). Blood samples were stored in CPD SAG-mannitol. The study of progressive reduction in the Elongation Index (EI) during the preservation may be used as way of evaluation of erythrocyte vitality in stored blood samples.

Adenine↗
PubMed1999

Reduced deformability of erythrocytes as feature of congenital dyserythropoietic anaemia type II (HEMPAS).

In this study we report results regarding erythrocytes deformability in congenital dyserythropoietic anemia type II (HEMPAS) by the use of LORCA (Laser-assisted Optical Rotational Cell Analyzer). The reduced erythrocytes deformability observed in seven case of CDA II is caused by changes in the structure of glycoproteins due to the incomplete glycosylation of erythrocytic and erythroblastic membrane. Erythrocytes deformability (EI) was shown to be inversely related with mean corpuscular volume (MCV) and mean haemoglobin concentration (MCH).

Adolescent↗
PubMed1998

A novel missense mutation Ile538Val in the fibroblast growth factor receptor 3 in hypochondroplasia. Mutations in brief no. 122. Online.

Hypochondroplasia and achondroplasia are skeletal dysplasias, characterized by autosomal dominant inheritance and disproportionate short stature, which occurs mainly due to growth failure of the extremities. Both dysplasias have been mapped to fibroblast growth factor receptor 3 (FGFR3) gene. For hypochondroplasia, two point mutations, both responsible for the Asn540Lys substitution in the region coding the tyrosine kinase domain have been reported. Here we report an A to G transition at position 1651, predicting an Ile538Val substitution in the FGFR3, in hypochondroplasia. The substitution is found in a swedish family with three affected members. The criteria for hypochondroplasia were disproportionate short stature and radiological evidence of shortened long bones and decrease or absence of normal increase in interpedicular distances of the lumbar column. The mutation was detected by direct sequencing and restriction enzyme Tai I digestion. The base change was not found in the FGFR3 genes of unaffected members of the family nor in seventy-five unrelated unaffected individuals, suggesting that it was not a polymorphism. The Ile538Val substitution is a conservative amino acid change (a hydrophobic amino acid incorporated for another hydrophobic amino acid). Nevertheless, it is located in the stretch of nine amino acids, which is highly conserved among all the human fibroblast growth factor receptors. Considering the location of this substitution and the segregation with the phenotype in this family, we propose that it is a causative mutation of hypochondroplasia. It is difficult to establish whether the Ile538Val substitution is rare in hypochondroplasia patients or whether the individuals, who have a moderate degree of short stature, rarely seek medical help for the short stature and consequently are rarely diagnosed as affected by hypochondroplasia.

Achondroplasia↗
PubMed1998

The familial adenomatous polyposis region exhibits many different haplotypes.

In the present study, we used five different polymorphic markers to construct the haplotype at the adenomatous polyposis coli (APC) locus in families with familial adenomatous polyposis (FAP) and in the normal Italian population. Non-ambiguous haplotypes were reconstructed from 246 normal chromosomes and 65 FAP chromosomes. In the control population, the four polymorphisms intragenic to APC gave rise to 16 haplotypes, the most common of which (II and XV) accounted for over 50% of all chromosomes. In FAP patients, 13 haplotypes were found but their distribution was not statistically different from normal subjects. Eighty complete chromosomal haplotypes (many fewer than the theoretical maximum of 208) for the five polymorphic sites assayed were observed in the control population, 35 being found in the FAP patients. We compared the distribution of these haplotypes within the two groups; no statistically significant differences between normal and FAP chromosomes were found. The elevated heterogeneity of FAP chromosomes was clearly confirmed by the observation that 19 patients who carried one or other of the two most common APC mutations (nt 3183 and nt 3927) showed 18 different haplotypes. On the basis of these results, we were not able to identify a founder FAP chromosome. Various mechanisms are presented to explain this observation.

Adenomatous Polyposis Coli↗
PubMed1998

hMLH1 mutations in hereditary nonpolyposis colorectal cancer kindreds. Mutations in brief no. 182. Online.

Hereditary nonpolyposis colorectral cancer (HNPCC), an autosomal dominantly inherited predisposition for early onset colorectal cancer, accounts for at least 6% of all colorectal malignancies. HNPCC results from germ-line mutations in DNA mismatch repair (MMR) genes (hMSH2, hMLH1, hPMS1 and hPMS2) and is associated with a high rate of replication errors in tumor cells. Using PCR-SSCP, the protein truncation test and DNA sequencing we have analyzed the hMSH2 and hMLH1 genes in 10 Italian families that met the standard diagnostic criteria for HNPCC. We have identified three new mutations in the hMLH1 gene. One mutation consists in a deletion of one base pair at nucleotide 954 (954delC) in exon 11 that creates an early stop at codon 366 and is predicted to abolish normal protein function. The other two are missense mutations. Cys77Arg and Ser193Pro, that cause dramatic amino acid substitutions in two highly conserved MLH domains. The Cys77Arg mutation occurs within a domain (1-114 residues) that is very critical for MMR function. The Ser193Pro mutation occurs in a highly conserved central region of the MLH1 protein. No functional domains have yet been identified in this region. All mutant alleles cosegregate with the cancer phenotype.

Adaptor Proteins, Signal Transducing↗