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Baglietto M.G.,Centro Epilessie | Caridi G.,Laboratorio Of Fisiopatologia Delluremia | Gimelli G.,Laboratorio Of Citogenetica | Mancardi M.,Centro Epilessie | And 4 more authors.
European Journal of Medical Genetics

Copy number variants represent an important cause of neurodevelopmental disorders including epilepsy, which is genetically determined in 40% of cases. Epilepsy is caused by chromosomal imbalances or mutations in genes encoding subunits of neuronal voltage- or ligand-gated ion channels or proteins related to neuronal maturation and migration during embryonic development. Here, we report on a girl with mild intellectual disability and idiopathic partial epilepsy. Array-CGH analysis showed a 1.040 Mb de novo interstitial deletion at 9q21.13 band encompassing only four genes, namely RORB, TRPM6, NMRK1, OSTF1, two open reading frames (C9orf40, C9orf41), and a microRNA (MIR548H3). RORB encodes a nuclear receptor highly expressed in the retina, cortex, and thalamus. We hypothesize its role in producing the phenotype of our patient and compare this case with other ones previously reported in the literature to better identify a genotype-phenotype correlation. © 2013 Elsevier Masson SAS. Source

Bachetti T.,CNR Institute of Molecular Genetics | Parodi S.,CNR Institute of Molecular Genetics | Di Duca M.,Laboratorio Of Fisiopatologia Delluremia | Santamaria G.,CNR Institute of Molecular Genetics | And 3 more authors.
Journal of Molecular Medicine

Heterozygous trinucleotide in frame duplications, leading to expansions of variable lengths of a 20-alanine stretch (polyAla), is the most frequent PHOX2B variant associated with congenital central hypoventilation syndrome (CCHS), a rare neurocristopathy characterized by defective response of the autonomic nervous system to hypoxia and hypercapnia. Sequencing analysis has shown that the vast majority of polyAla expansions arise de novo; while in about 10% of cases, mutations are inherited by one parent who carries either constitutive or somatic mutations. To investigate transmission of PHOX2B mutant alleles from asymptomatic individuals, we have reassessed 44 parental pairs, previously resulted not to carry any mutation, by coupling amplification with FAM-tagged primers and capillary electrophoresis. Low levels of somatic mosaicism were shown in five parents previously undetected, thus increasing the inherited occurrence of the disease from 10% to 25% of the cases. Analysis of the technical detection limits has confirmed a power of resolution much higher for the "FAM" protocol than for the "sequencing" method. These observations are going to have relevant implications on how the carrier status of asymptomatic parents should be assessed and on successive genetic counseling to CCHS families. © 2010 Springer-Verlag. Source

Lualdi S.,Ssd Laboratory Diagnosi Pre Postnatale Malattie Metaboliche | Tappino B.,Ssd Laboratory Diagnosi Pre Postnatale Malattie Metaboliche | Di Duca M.,Laboratorio Of Fisiopatologia Delluremia | Dardis A.,Centro Of Coordinamento Regionale Malattie Rare | And 9 more authors.
Human Mutation

Sequence analysis of the X-linked iduronate-2-sulfatase (IDS) gene in two Hunter syndrome patients revealed a lack of concordance between IDS genomic DNA and cDNA. These individuals were found to be hemizygous respectively for a nonsense mutation [c.22C>T;p.R8X] and a frameshift micro-insertion [c.10insT;p.P4Sfs] in their genomic DNA. However, both wild-type and mutant IDS sequences were evident upon cDNA analysis. Similar discrepant results were also obtained in a third unrelated patient carrying the same p.R8X mutation. Since both p.R8X mutations were inherited from carrier mothers, somatic mosaicism could be excluded. Although the presence of wild-type IDS mRNA-transcripts was confirmed in all three patients by restriction enzyme digestion, clone sequencing, pyrosequencing and single nucleotide primer extension (SNuPE), no wild-type IDS genomic sequence was detectable. The relative abundance of wild-type and mutation-bearing IDS-transcripts in different tissues was quantified by SNuPE. Although IDS transcript levels, as measured by real-time PCR, were reduced (51-71% normal) in these patients, some wild-type IDS protein was detectable by western blotting. Various possible explanations for these unprecedented findings (e.g. accidental contamination, artefactual in vitro nucleotide misincorporation, malsegregation of an extra maternal X-chromosome) were explored and experimentally excluded. PCR-based discriminant assay and segregation analysis of a linked IDS polymorphism (rs1141608) also served to exclude the presence of IDS cDNA derived from the maternal wild-type chromosome. Although it remains to be formally demonstrated by direct experimentation, the intriguing possibility arises that we have observed the in vivo correction of heritable gene lesions at the RNA level operating via a correction mechanism akin to RNA-editing. ©2010 Wiley-Liss, Inc. Source

Gimelli S.,University of Geneva | Leoni M.,USD Malattie Rare | Di Rocco M.,USD Malattie Rare | Caridi G.,Laboratorio Of Fisiopatologia Delluremia | And 4 more authors.
Molecular Cytogenetics

Background: Interstitial deletions affecting the proximal long arm of chromosome 3 have been rarely reported in the literature. The deleted segments vary in localization and size with different breakpoints making genotype-phenotype correlation very difficult. Until now, a girl with a 1.9-Mb interstitial deletion of 3q13.2q13.31 and 14 novel patients with deletions in 3q11q23 have been reported. Results: Here we report on a 7-year-old girl with neuropsychiatric disorders and renal, vascular and skeletal anomalies. Array-CGH analysis revealed a small rare inherited 3q13.31 deletion containing only two genes, GAP43 and LSAMP. The mutation analysis of the two genes was negative on the other non-deleted chromosome. GAP43 is considered a crucial component for an effective regenerative response in the nervous system and its mRNA is localized exclusively to nerve tissue where the protein is linked to the synaptosomal membrane. LSAMP is a 64- to 68-kD neuronal surface glycoprotein found in cortical and subcortical regions of the limbic system that acts as an adhesion molecule and guides the development of specific patterns of neuronal connection. The deleted region is adjacent to a "desert gene" region extending 2.099 Mb. Conclusions: We discuss the effects of GAP43 and LSAMP haploinsufficiency, proposing that their deletion may be responsible for the main phenotype. Further cases with similar microdeletion are expected to be diagnosed and will help to better characterize the clinical spectrum of phenotypes associated with 3q13.31 microdeletion. © 2013 Gimelli et al.; licensee BioMed Central Ltd. Source

Gimelli S.,University of Pavia | Gimelli S.,University of Geneva | Caridi G.,Laboratorio Of Fisiopatologia Delluremia | Beri S.,IRCCS E. Medea | And 12 more authors.
Human Mutation

Congenital anomalies of the kidney and the urinary tract (CAKUT) represent a major source of morbidity and mortality in children. Several factors (PAX, SOX,WNT, RET, GDFN, and others) play critical roles during the differentiation process that leads to the formation of nephron epithelia. We have identified mutations in SOX17, an HMG-box transcription factor and Wnt signaling antagonist, in eight patients with CAKUT (seven vesico-ureteric reflux, one pelvic obstruction). One mutation, c.775T>A (p.Y259N), recurred in six patients. Four cases derived from two small families; renal scars with urinary infection represented the main symptom at presentation in all but two patients. Transfection studies indicated a 5-10-fold increase in the levels of the mutant protein relative to wild-type SOX17 in transfected kidney cells. Moreover we observed a corresponding increase in the ability of SOX17 p.Y259N to inhibit Wnt/β-catenin transcriptional activity, which is known to regulate multiple stages of kidney and urinary tract development. In conclusion, SOX17 p.Y259N mutation is recurrent in patients with CAKUT. Our data shows that this mutation correlates with an inappropriate accumulation of SOX17-p.Y259N protein and inhibition of the β-catenin/Wnt signaling pathway. These data indicate a role of SOX17 in human kidney and urinary tract development and implicate the SOX17-p.Y259N mutation as a causative factor in CAKUT. © 2010 Wiley-Liss, Inc. Source

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