IRCCS CSS Mendel Institute

Rome, Italy

IRCCS CSS Mendel Institute

Rome, Italy
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Bertolino A.,University of Bari | Taurisano P.,University of Bari | Pisciotta N.M.,University of Bari | Blasi G.,University of Bari | And 17 more authors.
PLoS ONE | Year: 2010

Background: Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods: Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results: Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [ 123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions: Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic- cortical pathway. © 2010 Bertolino et al.

Covaciu C.,Instituto Dermopatico dellImmacolata IRCCS | Grosso F.,Instituto Dermopatico dellImmacolata IRCCS | Pisaneschi E.,IRCCS CSS Mendel Institute | Zambruno G.,Instituto Dermopatico dellImmacolata IRCCS | And 4 more authors.
British Journal of Dermatology | Year: 2011

Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) (OMIM 604129) represents a distinct variant within the DEB clinical spectrum. It is characterized by intense pruritus and distinctive nodular prurigo-like and/or hypertrophic lichenoid lesions mainly localized on the arms, legs and upper shoulders. DEB-Pr is caused by either dominant (DDEB-Pr) or recessive mutations in the COL7A1 gene encoding type VII collagen (COLVII). The full spectrum of COL7A1 mutations in DEB-Pr remains elusive and the genotype-phenotype correlation is largely incomplete. Here, we report and functionally characterize a previously unrecognized translationally silent exonic COL7A1 mutation that results in skipping of exon 87 and is associated with DDEB-Pr phenotypes in several members of three apparently unrelated Danish families. A haplotype segregation study suggested a common ancestor in these kindred. Functional splicing analysis of the mutant exon by a COL7A1 minigene construct and computational prediction for splicing regulatory cis-sequences prove that the mutation alters the activity of an exonic splicing enhancer (ESE) critical for exon inclusion. These findings substantiate for the first time the involvement of an ESE mutation in the pathogenesis of DEB and have implications for genetic counselling of Danish families with DDEB. © 2011 British Association of Dermatologists.

Giuliani R.,University of Chieti Pescara | Antonucci I.,University of Chieti Pescara | Torrente I.,IRCCS CSS Mendel Institute | Grammatico P.,University of Rome | And 5 more authors.
Asian Journal of Andrology | Year: 2010

Congenital bilateral absence of vas deferens (CBAVD) is a manifestation of the mildest form of cystic fibrosis (CF) and is characterized by obstructive azoospermia in otherwise healthy patients. Owing to the availability of assisted reproductive technology, CBAVD patients can father children. These fathers are at risk of transmitting a mutated allele of the CF transmembrane conductance regulator (CFTR) gene, responsible for CF, to their offspring. The identification of mutations in both CFTR alleles in CBAVD patients is a crucial requirement for calculating the risk of producing a child with full-blown CF if the female partner is a healthy CF carrier. However, in the majority of CBAVD patients, conventional mutation screening is not able to detect mutations in both CFTR alleles, and this difficulty hampers the execution of correct genetic counselling. To obtain information about the most represented CFTR mutations in CBAVD patients, we analysed 23 CBAVD patients, 15 of whom had a single CFTR mutation after screening for 36 mutations and the 5T allele. The search for the second CFTR mutation in these cases was performed by using a triplex approach: (i) first, a reverse dot-blot analysis was performed to detect mutations with regional impact; (ii) next, multiple ligation-dependent probe amplification assays were conducted to search for large rearrangements; and (iii) finally, denaturing high-performance liquid chromatography was used to search for point mutations in the entire coding region. Using these approaches, the second CFTR mutation was detected in six patients, which increased the final detection rate to 60.8%. © 2010 AJA, SIMM & SJTU All rights reserved.

Modoni A.,Catholic University | D'Amico A.,Bambino Gesu Research Pediatric Hospital | Dallapiccola B.,IRCCS CSS Mendel Institute | Dallapiccola B.,University of Rome La Sapienza | And 9 more authors.
Journal of Clinical Neurophysiology | Year: 2011

Transitory depression of the compound muscle action potential during repetitive nerve stimulation is a well-documented neurophysiologic finding in recessive myotonia congenita. It represents the neurophysiologic counterpart of the transitory weakness often impairing patients at the beginning of a movement after rest, and it is usually better induced using high-rate nerve stimulations. The authors examined 30 patients with recessive myotonia congenita and carried out a 3 Hz nerve stimulation study to ascertain to what extent this protocol was able to detect the occurrence of transitory depression. Their findings were compared with the results obtained by 12 patients affected by dominant myotonia congenita and 12 patients affected by nondystrophic myotonia due to SCN4A mutations. Molecular genetic analysis of the CLCN1 and SCN4A genes was also performed. The 3 Hz nerve stimulation protocol was well tolerated and showed high sensitivity, resulting positive in 66% of recessive case and good reproducibility, if performed after an adequate period of rest. All dominant cases and all patients affected by myotonia due to SCN4A mutations showed negative results. Molecular studies identified 26 different CLCN1 mutations, 16 of which were novel. Transitory depression confirmed to vary in accordance to CLCN1 mutations. The 3 Hz protocol was well tolerated and showed good sensitivity and reproducibility. Furthermore, this test might be suitable for genotype-phenotype correlation studies. Copyright © 2011 by the American Clinical Neurophysiology Society.

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