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Mauro D'Amato

Publications and source records attributed to Mauro D'Amato.

7 recordsLinked to original sources
PubMed2007

Potential role for the common cystic fibrosis DeltaF508 mutation in Crohn's disease.

BACKGROUND: Inflammatory bowel disease (IBD) is an epithelial barrier disease that is thought to result from a dysregulated interaction with bacteria in the intestine of genetically predisposed individuals. The cystic fibrosis transmembrane conductance regulator (CFTR), which is mutated in the autosomal recessive disease cystic fibrosis, modulates gut permeability, mucus production, and epithelial interactions with bacteria. The cystic fibrosis DeltaF508 mutation is commonly found in the general population and has been shown to result in a reduced number of CFTR molecules at the surface of epithelial cells. Given the important biological functions of CFTR in the intestine, we tested whether this mutation is of relevance to IBD. METHODS: Using DNA heteroduplex analysis, we investigated the distribution of DeltaF508 heterozygosity in 2568 subjects from three independent cohorts of Italian, Swedish, and Scottish IBD patients and controls. RESULTS: In all three cohorts an association between DeltaF508 and Crohn's disease (CD) was observed. Specifically, DeltaF508 heterozygosity was markedly underrepresented in CD patients from Italy and Sweden (P = 0.021 and 0.027 versus controls, respectively), while stratification for disease location revealed an absence of DeltaF508 carriers among Scottish CD patients with right-sided colitis (P = 0.023 versus all other locations). CONCLUSIONS: DeltaF508 heterozygosity might exert a protective effect in CD.

Adolescent↗
PubMed2005

Functional interaction of CARD15/NOD2 and Crohn's disease-associated TNFalpha polymorphisms.

BACKGROUND AND AIMS: Mutations/polymorphisms in the CARD15/NOD2 gene and in the promoter region of the TNFalpha gene are associated with susceptibility to and modulate the phenotype of Crohn's disease (CD). The molecular mechanisms for this genotype-phenotype correlation are yet to be elucidated. CARD15 is an intracellular receptor for bacterial muramyl dipeptide (MDP), and can elicit an inflammatory response via activation of the NF-kappaB pathway. MDP is also known to induce the expression of pro-inflammatory cytokines including TNFalpha, through a still poorly characterized signaling pathway. We sought to determine whether CARD15-mediated NF-kappaB activation can contribute to MDP-induced TNFalpha production and, consequently, if polymorphisms in both genes affect the control of such induction. METHODS/RESULTS: Transfection and electrophoretic mobility shift assays (EMSA) experiments in HEK293 cells demonstrated that MDP exposure stimulates TNFalpha gene transcription, as a result of CARD15-induced NF-kappaB activation and binding to TNFalpha promoter. When the CD-associated CARD15 1007fs variant was analyzed, induction of TNFalpha promoter activity was found to be defective. Different combinations of CARD15 and TNFalpha promoter polymorphisms gave rise to distinct TNFalpha transcription levels. CONCLUSIONS: CARD15 and TNFalpha promoter polymorphisms interact to exert a functional effect on MDP-induced TNFalpha production. This gene-gene interaction may contribute to interindividual variation in susceptibility to, and manifestation of, Crohn's disease.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2004

Malassezia sympodialis stimulation differently affects gene expression in dendritic cells from atopic dermatitis patients and healthy individuals.

It is known that 28-84% of patients with atopic dermatitis exhibit IgE and/or T-cell reactivity to the opportunistic yeast Malassezia sympodialis, which can be taken up by immature monocyte-derived dendritic cells (MDDCs), resulting in MDDC maturation. The aim of this study was to investigate whether MDDCs from patients with atopic dermatitis respond differently to M. sympodialis compared to MDDCs from healthy individuals. Immature MDDCs were stimulated with M. sympodialis and the gene expression profiles were analysed with cDNA arrays containing 406 genes. Our results show that M. sympodialis differently affected MDDCs from patients with atopic dermatitis, and more so in severely ill patients, compared with healthy individuals. Six genes were more than fivefold up-regulated in MDDCs from more than one patient with atopic dermatitis, coding for CD54, CD83, IL-8, monocyte-derived chemokine (MDC), BTG1 and IL-1R antagonist. In healthy individuals this was true only for BTG1. Up-regulations of IL-8 and MDC were confirmed at the protein level. Our findings might reflect an increased trafficking and stimulatory capacity in MDDCs from the patients, which is likely to result in a stronger inflammatory response to M. sympodialis.

Adult↗
PubMed2004

Improved allelic differentiation using sequence-specific oligonucleotide hybridization incorporating an additional base-analogue mismatch.

Sequence-specific oligonucleotide hybridization (SSOH, 'dot-blotting') is a widely employed method of typing single nucleotide polymorphisms (SNPs), but it is often compromised by lack of allelic differentiation. We describe a novel improvement to SSOH that incorporates an additional mismatch into the oligonucleotide probe using the universal base analogue 3-nitropyrrole. This method greatly increases allelic differentiation compared to standard SSOH where oligonucleotides contain only SNP-defining base changes. Moreover, stringency of the hybridisation is predictably maintained over a wide range of temperatures, which can be calculated empirically, thus facilitating the genotyping of multiple SNPs using similar conditions. This improved method increases the usefulness of hybridisation-based methods of rapid genotyping of SNPs and may have implications for array methodologies.

Alleles↗
PubMed2003

LD mapping of maternally and non-maternally derived alleles and atopy in FcepsilonRI-beta.

Polymorphisms in the beta chain of the high affinity receptor for IgE (Fc epsilon RI-beta, MS4A2) are consistently associated with traits underlying asthma and atopy (immunoglobulin E-mediated allergy). However, the causal variants and haplotypes underlying disease have not yet been identified. Maternal effects, with association confined to maternally derived alleles, have been shown in some studies but not in others. We have therefore extended the known sequence and systematically detected polymorphisms across an 18.1 Kb genomic region that includes Fc epsilon RI-beta. Association testing in two panels of subjects showed the presence of single-nucleotide polymorphisms (SNPs) affecting prick skin tests and specific IgE responses in several clusters. Stepwise analyses indicated that the clusters represent independent effects. Interferon regulatory factor 2 (IRF-2) sites were altered by significantly associated SNPs in two regions. Strong association to maternally derived alleles was seen in one panel of subjects and not in the other. Maternal and non-maternally derived associations tended to share the same SNP clusters, but associations were stronger in the presence of maternal effects. Two regions of increased CpG concentration were identified in Fc epsilon RI-beta. One of these approximated a SNP cluster that showed strong association and maternal effects, providing a potential substrate for epigenetic effects.

Alleles↗
PubMed2003

Genetic analysis of variegate porphyria (VP) in Italy: identification of six novel mutations in the protoporphyrinogen oxidase (PPOX) gene.

Variegate Porphyria (VP) is one of the acute hepatic porphyrias, and is clinically characterised by skin lesions and acute neuropsychiatric/visceral attacks that occur separately or together. The disorder is caused by a partial deficiency of protoporphyrinogen oxidase, the penultimate enzyme in the heme biosynthetic pathway, and a number of mutations have been described for the corresponding gene (PPOX). Here we report a genetic analysis of VP in Italy, and the identification of six novel and three previously characterised mutations from nine affected individuals and families. Among those newly identified, two mutations were small deletions (c.418_419delAA; c.759delA), leading to the formation of premature stop codons, two were splicing defects (IVS10+2T>G; IVS12+1G>C), one was a nonsense (c.384G>A=p.W128X) and one a missense mutation (c.848T>A=I283N). This is the first study of the molecular genetics of Variegate Porphyria in patients of Italian origin, and the finding of six novel mutations out of nine identified confirms the genetic heterogeneity observed for this disorder.

Adult↗