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Biomedical subjects

Bruno Dallapiccola

Publications and source records attributed to Bruno Dallapiccola.

At least 55 records · Page 3Linked to original sources
PubMed2006

Relationship between CARD15, SLC22A4/5, and DLG5 polymorphisms and early-onset inflammatory bowel diseases: an Italian multicentric study.

BACKGROUND: Inflammatory bowel disease (IBD) has been associated with several polymorphisms in genes likely involved in innate immune responses and integrity of epithelial mucosal barrier. A major role in adult Crohn's disease (CD) has been defined for 3 polymorphisms in the CARD15 gene, whereas variants in the SLC22A4, SLC22A5, and DLG5 genes could have a minor contribution to IBD susceptibility. METHODS: We analyzed a panel of 6 polymorphisms within these genes in 227 Italian early-onset IBD patients (134 CD, 93 ulcerative colitis [UC]; age at diagnosis <or=18 years) and 166 unaffected control subjects. RESULTS: Each CARD15 variant was found to be independently associated with CD. After the genotypes at the 3 polymorphisms were combined, 37.3% patients carried at least 1 variant compared with 9.2% control subjects (odds ratio, 5.87; 95% CI 3.11-11.1; P < 0.001). The combined frequency of CARD15 variants was also higher in UC children compared with control subjects (14% vs 9.2%), but this difference was not significant. However, CARD15 variants were associated with earlier onset of UC, and the mutation rate was significantly higher in UC patients with onset at or before 6 years of age compared with control subjects (27.6% vs 9.2%) (odds ratio = 3.76; 95% CI 1.42-9.94; P = 0.01). CARD15 variants also were associated with ileal CD involvement and a higher rate of extraintestinal manifestations in UC. Allele and genotype frequencies at SLC22A and DLG5 polymorphisms were not significantly different between cases and controls. CONCLUSIONS: Our results demonstrate that in the Italian population, the major CARD15 polymorphisms are associated with susceptibility to early-onset CD and with ileal involvement and suggest a previously unreported association with very early-onset, severe UC.

Adolescent↗
PubMed2006

Contribution of IBD5 locus to clinical features of IBD patients.

AIM: The aim of this study was to investigate the influence of the IBD5 locus on clinical features of inflammatory bowel disease (IBD) patients, and its possible interaction with the CARD15 gene. PATIENTS AND METHODS: A cohort of 1,199 IBD patients (570 with CD and 629 with ulcerative colitis [UC]), and 357 healthy subjects were investigated. Information on clinical features was fully available for 855 IBD patients. Two SNPs in the IBD5 locus (IGR2198a_1 and IGR2096a_1) and the three major variants of CARD15 gene were genotyped in patients and controls. RESULTS: Homozygous carriers of risk alleles were significantly more frequent in CD (22.6% for IGR2198a_1, OR = 1.6, p = 0.015; 21.9% for IGR2096a_1, OR = 1.6, p = 0.012) compared to controls (16.8% and 15.7%, respectively). The homozygote frequency was also increased in UC patients, but not significantly. No significant gene-gene interaction was detected between IBD5 and CARD15. A univariate analysis detected association between IBD5 and steno/fistulizing behavior in CD patients (OR = 1.9; p = 0.004), and presence of more extensive colitis in UC patients (OR = 1.7; p = 0.01). Results from multiple logistic regression, after correction for covariates, showed that the influence of IBD5 on clinical outcome of CD was completely masked by that of CARD15, while the influence on more extensive colitis in UC patients was confirmed. CONCLUSIONS: Our study shows that presence of the IBD5 risk alleles, particularly in the homozygous state, is associated with IBD and especially with CD, without a significant epistasis with CARD15. The contribution of CARD15 risk alleles to CD clinical features is prominent on that of IBD5.

Adolescent↗
PubMed2006

DHPLC screening of ATM gene in Italian patients affected by ataxia-telangiectasia: fourteen novel ATM mutations.

The gene for ataxia-telangiectasia (A-T:MIM: #208900), ATM, spans about 150 kb of genomic DNA and is composed of 62 coding exons. ATM mutations are found along the entire coding sequence of the gene, without evidence of mutational hot spots. Using DNA as the starting material, we used denaturing high performance liquid chromatography (DHPLC) technique to search for ATM gene mutations. Initially, DHPLC was validated in a retrospective study of 16 positive control samples that included 19 known mutations; 100% of mutations were detected. Subsequently, DHPLC was used to screen for mutations a cohort of 22 patients with the classical form of A-T. A total of 27 different mutations were identified on 38 of the 44 alleles, corresponding to a 86% detection rate. Fourteen of the mutations were novel. In addition, 15 different variants and polymorphisms of unknown functional significance were found. The high incidence of new and individual A-T mutations in our cohort of patients demonstrates marked mutational heterogeneity of A-T in Italy and corroborate the efficiency of DHPLC as a method for the mutation screening of A-T patients.

Ataxia Telangiectasia↗
PubMed2006

22q11 deletion syndrome: a review of some developmental biology aspects of the cardiovascular system.

The morphology and molecular genetics of the 22q11 deletion syndrome cardiovascular anomalies are reviewed. Special emphasis is given to TBX1, recently identified and considered to be the potential key gene for this clinical syndrome. The TBX1 downstream molecular pathways modulating the normal development of the pharyngeal apparatus are also discussed, and emphasis is given to the possible, equally fundamental role of downstream molecular pathway disruption in causing the clinical 22q11 deletion phenotype features.

Animals↗
PubMed2006

Influence of Ggamma-158C --> and beta- (AT)x(T)y globin gene polymorphisms on HbF levels in Italian beta-thalassemia carriers and wild-type subjects.

Clinical manifestations of beta-thalassemia (beta-thal) intermedia phenotypes are influenced by the persistence of fetal hemoglobin (HbF) and by several polymorphisms located in the promoters of A- and beta-globin genes. The aim of this study was to evaluate the distribution of the -158Ggamma (C-->T) polymorphism and of the (AT)x(T)y configuration, as well as their eventual association with elevated levels of HbF in 188 beta-thal carriers and 229 wild-type individuals of Italian descent. The -158GgammaT and the (AT)9(T)5alleles were found to be associated with increased levels of HbF in beta-thal carriers, but not in wild-type subjects.

Fetal Hemoglobin↗
PubMed2005

Majewski osteodysplastic primordial dwarfism type II (MOPD II) complicated by stroke: clinical report and review of cerebral vascular anomalies.

We report on a 2 9/12-year-old boy with disproportionate short stature, microcephaly, subtle craniofacial dysmorphisms, and generalized skeletal dysplasia, who developed a left hemiparesis. Brain neuroimaging disclosed a complex cerebral vascular anomaly (CVA) with stenosis of the right anterior cerebral artery and telangiectatic collateral vessels supplying the cerebral cortex, consistent with moyamoya disease. Based on clinical and skeletal features, a diagnosis of Majewski osteodysplastic primordial dwarfism type II (MOPD II) was established. Review of 16 published patients with CVA affected by either Seckel syndrome or MOPD II suggested that CVA is preferentially associated to the latter subtype affecting about 1/4 of the patients.

Abnormalities, Multiple↗
PubMed2005

NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome.

Neurofibromatosis type 1 (NF1) demonstrates phenotypic overlap with Noonan syndrome (NS) in some patients, which results in the so-called neurofibromatosis-Noonan syndrome (NFNS). From a genetic point of view, NFNS is a poorly understood condition, and controversy remains as to whether it represents a variable manifestation of either NF1 or NS or is a distinct clinical entity. To answer this question, we screened a cohort with clinically well-characterized NFNS for mutations in the entire coding sequence of the NF1 and PTPN11 genes. Heterozygous NF1 defects were identified in 16 of the 17 unrelated subjects included in the study, which provides evidence that mutations in NF1 represent the major molecular event underlying this condition. Lesions included nonsense mutations, out-of-frame deletions, missense changes, small inframe deletions, and one large multiexon deletion. Remarkably, a high prevalence of inframe defects affecting exons 24 and 25, which encode a portion of the GAP-related domain of the protein, was observed. On the other hand, no defect in PTPN11 was observed, and no lesion affecting exons 11-27 of the NF1 gene was identified in 100 PTPN11 mutation-negative subjects with NS, which provides further evidence that NFNS and NS are genetically distinct disorders. These results support the view that NFNS represents a variant of NF1 and is caused by mutations of the NF1 gene, some of which have been demonstrated to cause classic NF1 in other individuals.

Child↗
PubMed2005

Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism.

Parkinson's disease (PD) is a progressive neurodegenerative illness associated with a selective loss of dopaminergic neurons in the nigrostriatal pathway of the brain. Despite the overall rarity of the familial forms of PD, the identification of single genes linked to the disease has yielded crucial insights into possible mechanisms of neurodegeneration. Recently, a putative mitochondrial kinase, PINK1, has been found mutated in an inherited form of parkinsonism. Here, we describe that PINK1 mutations confer different autophosphorylation activity, which is regulated by the C-terminal portion of the protein. We also demonstrate the mitochondrial localization of both wild-type and mutant PINK1 proteins unequivocally and prove that a short N-terminal part of PINK1 is sufficient for its mitochondrial targeting.

Amino Acid Sequence↗
PubMed2005

Familial recurrence of heart defects in subjects with congenitally corrected transposition of the great arteries.

Familial recurrence of congenitally corrected transposition of the great arteries (CCTGA) is considered uncommon. Most of the previous familial studies involved a small number of patients and referred to all situs and looping anomalies including single ventricle, heterotaxia, and other cardiac defects different from CCTGA. We performed a large, consecutive clinical case series study in order to detect the recurrence of congenital heart defects in families of children with the classic form of CCTGA. From January 1997 through December 2004, 102 consecutive patients with CCTGA were evaluated in four institutions. There were 59 male (57.8%) and 43 female (42.2%). Mean age was 8.6 +/- 7.8 years. Eighty-eight patients (86.3%) had situs solitus of the atria, 14 (13.7%) situs inversus. The cardiac and extracardiac anomalies among relatives and the patterns of familial recurrence were investigated. Relatives with congenital heart defects were found in 16/102 families (15.7%). Transposition of the great arteries (TGA) was the most common recurrent defect (6/102 families). Consanguinity was identified in the parents of three probands. Six probands had an unaffected twin-sib. Recurrence risks for congenital heart defects were calculated at 5.2% (6/116) for siblings. In conclusion, CCTGA is not always sporadic in families. The pattern of inheritance, the presence of consanguinity among parents and the recurrence of situs inversus could suggest, in some families, an autosomal recessive mechanism with similarities with that occurring in some pedigrees with heterotaxia. The recurrence of TGA and CCTGA in the same family suggests a pathogenetic link between these two anatomically different malformations.

Family Health↗
PubMed2005

A new observation of acro-cardio-facial syndrome substantiates interindividual clinical variability.

We report on a baby presenting with ectrodactyly, heart defects, and mild facial dysmorphisms, an association recognized as acro-cardio-facial syndrome (ACFS). Based on the first three observations, the acronym CCGE, cleft palate, cardiac defect, genital anomalies, and ectrodactyly had been proposed to embrace the most consistent features of this syndrome. A subsequent report and the present patient point to an obvious interindividual and intrafamilial variability of this autosomal recessive disorder in which ectrodactyly was the sole characteristic shared by all affected individuals.

Abnormalities, Multiple↗
PubMed2005

Familial recurrence of nonsyndromic congenital heart defects in first degree relatives of patients with deletion 22q11.2.

The majority of nonsyndromic congenital heart defects (CHDs) are considered to follow a multifactorial model of inheritance. Multiple family members affected by CHD can occasionally be detected, and the involvement of several genetic loci interacting with environmental factors is suspected to be implicated. The DiGeorge/velo-cardio-facial syndrome related to microdeletion 22q11.2 (del22) is a genetic condition associated with CHD in most of the cases. We report here on five pedigrees of patients with del22, showing occurrence of nonsyndromic CHD in a first-degree relative of the proband case. Familial aggregation of syndromic and nonsyndromic CHD as observed in our series is to be considered as an unusual pattern of recurrence. The interaction between several different genes and environmental factors, a familial susceptibility predisposing to a specific cardiac malformation, or chance association can all be hypothesized searching an explanation for these particular observations.

Chromosome Deletion↗