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PubMed | University of Sfax, Laboratory of Medical Genetics and Neonatology Service
Type: Case Reports | Journal: Molecular biology reports | Year: 2016

Donohue syndrome (DS) is a very rare autosomal recessive disease affecting less than one in a million life births. It represents the most severe form of insulin resistance due to mutations involving the insulin receptor (IR) gene INSR. DS is characterized by pre- and postnatal growth retardation with failure-to-thrive, lipoatrophy, acanthosis nigricans, hypertrichosis, and dysmorphic features. An exhaustive INSR gene sequencing was performed after PCR amplification of coding exons and introns boundaries. Bioinformatic tools, including ESEfinder, MFOLD and Proter software were also used to predict the impact of INSR mutation on INSR on gene expression as well as on the protein structure and function. The results have shown a novel unusual c.3003_3012delinsGGAAG (p.S1001_D1004delinsRE) insertion/deletion (indel) mutation within the exon 16 in the three patients, which represent the fourth indel mutation within the INSR gene. The mutation modifies the secondary structure of DNA and RNA, as well as the composition of exonic splicing enhancers of exon 16. Moreover, despite the conservation of the secondary structure of the IR, the p.S1001_D1004delinsRE in-frame mutation is accompanied by the loss of four amino acids replaced by two residues of different nature and hydrophobicity level in the juxtamembrane domain of the receptor. The results have confirmed the role of the juxtamembrane domain of IR involved in a crucial interaction of the IR with cellular effectors essentially the IR substrate 1 (IRS-1), the SHC and the Nck proteins that ensure the signal mediated by the insulin transduction pathway in target cells. Our findings have also proven the genotype/phenotype correlation between INSR mutation and DS phenotype severity.


PubMed | University of Piemonte Orientale, Laboratory of Medical Genetics, University of Bologna, Pediatric Cardiology Unit and and 4 more.
Type: Journal Article | Journal: Pediatrics | Year: 2016

Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli (STEC-HUS) is a severe acute illness without specific treatment except supportive care; fluid management is concentrated on preventing fluid overload for patients, who are often oligoanuric. Hemoconcentration at onset is associated with more severe disease, but the benefits of volume expansion after hemolytic uremic syndrome (HUS) onset have not been explored.All the children with STEC-HUS referred to our center between 2012 and 2014 received intravenous infusion targeted at inducing an early volume expansion (+10% of working weight) to restore circulating volume and reduce ischemic or hypoxic tissue damage. The short- and long-term outcomes of these patients were compared with those of 38 historical patients referred to our center during the years immediately before, when fluid intake was routinely restricted.Patients undergoing fluid infusion soon after diagnosis showed a mean increase in body weight of 12.5% (vs 0%), had significantly better short-term outcomes with a lower rate of central nervous system involvement (7.9% vs 23.7%, P = .06), had less need for renal replacement therapy (26.3% vs 57.9%, P = .01) or intensive care support (2.0 vs. 8.5 days, P = .02), and needed fewer days of hospitalization (9.0 vs 12.0 days, P = .03). Long-term outcomes were also significantly better in terms of renal and extrarenal sequelae (13.2% vs 39.5%, P = .01).Patients with STEC-HUS had great benefit from early volume expansion. It is speculated that early and generous fluid infusions can reduce thrombus formation and ischemic organ damage, thus having positive effects on both short- and long-term disease outcomes.


PubMed | Urbino University, Wistar Institute, Italian National Cancer Institute, Laboratory of Medical Genetics and 3 more.
Type: | Journal: Oncotarget | Year: 2016

Lung cancer is the leading cause of tumor-related death worldwide and more efforts are needed to elucidate lung carcinogenesis. Here we investigated the expression of 641 miRNAs in lung tumorigenesis in a K-Ras(+/LSLG12Vgeo);RERTn(ert/ert) mouse model and 113 human tumors. The conserved miRNA cluster on chromosome 12qF1 was significantly and progressively upregulated during murine lung carcinogenesis. In particular, miR-494-3p expression was correlated with lung cancer progression in mice and with worse survival in lung cancer patients. Mechanistically, ectopic expression of miR-494-3p in A549 lung cancer cells boosted the tumor-initiating population, enhanced cancer cell motility, and increased the expression of stem cell-related genes. Importantly, miR-494-3p improved the ability of A549 cells to grow and metastasize in vivo, modulating NOTCH1 and PTEN/PI3K/AKT signaling.Overall, these data identify miR-494-3p as a key factor in lung cancer onset and progression and possible therapeutic target.


PubMed | Medical Genetics Unit, University of Milan and Laboratory of Medical Genetics
Type: Journal Article | Journal: European journal of medical genetics | Year: 2016

De novo interstitial deletions of the short arm of chromosome 2 are rare chromosomal abnormalities. Patients showing these kind of microdeletions have developmental delay/intellectual disability, minor facial anomalies including high forehead, frontal bossing, broad nasal bridge, abnormal ears and congenital defects such as skeletal and genital malformations. We describe the second child of a healthy and non consanguineous couple presenting at birth multiple malformations and minor facial anomalies. Because of the clinical findings, an array CGH analysis was performed using Agilent 60K microarray oligonucleotide. The analysis detected a 9.3Mb deletion on the short arm of chromosome 2 at band p11.2p12 spanning the bases 77,946,599-87,277,610. The five patients previously described display a minimal common deleted region which explains the clinical features shared by all of them, while their individual characteristics might be explained by the different sizes of the deletion. The common deleted region involves several genes (CTNNA2, LRRTM1, REEP1), highly expressed in the nervous system. The deletion found in this case overlaps with most of those reported in literature but our patient displays extra clinical signs such as bilateral choanal atresia and atrial septal defect. It was impossible to find any direct correlation between the genes involved in the deletion and the choanal atresia and the heart defect. The question remains open as to whether these clinical features are a consequence of the deletion or are due to a second pathogenic event. Our case emphasizes the difficulties to find a close correlation between a large deletion and a well defined clinical picture. As only five patients with 2p11.2p12 deletions, reported in the literature are characterized by array CGH, further reports will be necessary to well define a clinical phenotype related to the 2p11.2p12 microdeletion.


Pillai-Kastoori L.,University of Kentucky | Wen W.,University of Kentucky | Wilson S.G.,University of Kentucky | Strachan E.,University of Alberta | And 6 more authors.
PLoS Genetics | Year: 2014

Ocular coloboma is a sight-threatening malformation caused by failure of the choroid fissure to close during morphogenesis of the eye, and is frequently associated with additional anomalies, including microphthalmia and cataracts. Although Hedgehog signaling is known to play a critical role in choroid fissure closure, genetic regulation of this pathway remains poorly understood. Here, we show that the transcription factor Sox11 is required to maintain specific levels of Hedgehog signaling during ocular development. Sox11-deficient zebrafish embryos displayed delayed and abnormal lens formation, coloboma, and a specific reduction in rod photoreceptors, all of which could be rescued by treatment with the Hedgehog pathway inhibitor cyclopamine. We further demonstrate that the elevated Hedgehog signaling in Sox11-deficient zebrafish was caused by a large increase in shha transcription; indeed, suppressing Shha expression rescued the ocular phenotypes of sox11 morphants. Conversely, over-expression of sox11 induced cyclopia, a phenotype consistent with reduced levels of Sonic hedgehog. We screened DNA samples from 79 patients with microphthalmia, anophthalmia, or coloboma (MAC) and identified two novel heterozygous SOX11 variants in individuals with coloboma. In contrast to wild type human SOX11 mRNA, mRNA containing either variant failed to rescue the lens and coloboma phenotypes of Sox11-deficient zebrafish, and both exhibited significantly reduced transactivation ability in a luciferase reporter assay. Moreover, decreased gene dosage from a segmental deletion encompassing the SOX11 locus resulted in microphthalmia and related ocular phenotypes. Therefore, our study reveals a novel role for Sox11 in controlling Hedgehog signaling, and suggests that SOX11 variants contribute to pediatric eye disorders. © 2014 Pillai-Kastoori et al.


Henrichsen C.N.,University of Lausanne | Csardi G.,University of Lausanne | Csardi G.,Swiss Institute of Bioinformatics | Zabot M.-T.,Groupement Hospitalier Est | And 5 more authors.
PLoS Computational Biology | Year: 2011

The genetic dissection of the phenotypes associated with Williams-Beuren Syndrome (WBS) is advancing thanks to the study of individuals carrying typical or atypical structural rearrangements, as well as in vitro and animal studies. However, little is known about the global dysregulations caused by the WBS deletion. We profiled the transcriptomes of skin fibroblasts from WBS patients and compared them to matched controls. We identified 868 differentially expressed genesthat were significantly enriched in extracellular matrix genes, major histocompatibility complex (MHC) genes, as well as genes in which the products localize to the postsynaptic membrane. We then used public expression datasets from human fibroblasts to establish transcription modules, sets of genes coexpressed in this cell type. We identified those sets in which the average gene expression was altered in WBS samples. Dysregulated modules are often interconnected and share multiple common genes, suggesting that intricate regulatory networks connected by a few central genes are disturbed in WBS. This modular approach increases the power to identify pathways dysregulated in WBS patients, thus providing a testable set of additional candidates for genes and their interactions that modulate the WBS phenotypes. © 2011 Henrichsen et al.


PubMed | Genetica Medica, Paediatrics and Medical Genetics Unit, University of Cambridge, University of Siena and Laboratory of Medical Genetics
Type: Journal Article | Journal: Journal of human genetics | Year: 2016

Methyl-CpG-binding protein 2 (MeCP2) is a nuclear protein highly expressed in neurons that is involved in transcriptional modulation and chromatin remodeling. Mutations in MECP2 in females are associated with Rett syndrome, a neurological disorder characterized by a normal neonatal period, followed by the arrest of development and regression of acquired skills. Although it was initially thought that MECP2 pathogenic mutations in males were not compatible with life, starting from 1999 about 60 male patients have been identified and their phenotype varies from severe neonatal encephalopathy to mild intellectual disability. Targeted next-generation sequencing of a panel of intellectual disability related genes was performed on two unrelated male patients, and two missense variants in MECP2 were identified (p.Gly185Val and p.Arg167Trp). These variants lie outside the canonical methyl-CpG-binding domain and transcription repression domain domains, where the pathogenicity of missense variants is more difficult to establish. In both families, variants were found in all affected siblings and were inherited from the asymptomatic mother, showing skewed X-chromosome inactivation. We report here the first missense variant located in AT-hook domain 1 and we underline the importance of MECP2 substitutions outside the canonical MeCP2 domains in X-linked intellectual disability.


PubMed | The Second University of Naples, Cardiomyology and Medical Genetics and Laboratory of Medical Genetics
Type: Journal Article | Journal: Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | Year: 2016

Mutations in the lamin A/C gene (LMNA) have been associated with several phenotypes ranging from systemic to prevalent of muscle, heart, skin, nerve etc. More recently they have been associated with dilated cardiomyopathy (DCM) and severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). We report four novel mutations - 3 missense and 1 deletion - in 4 unrelated patients showing different phenotypes, ranging from the early onset congenital form of laminopathy to classical LGMD phenotype, to LGMD and heart involvement. All these newly identified variants were not found in 300 ethnicallymatched control subjects. The variant c.103-105del CTG was described post-mortem in a young patient with congenital muscular dystrophy who presented at the age of 9 a first degree A-V block and subsequently several episodes of supraventricular parossystic tachycardia. Two patients presented as onset symptom lower limbs muscle weakness, and developed heart conduction defects requiring pacemaker implantation at the age of 26 and 38 years, respectively. One of them who carried the mutation c.1339G>C died at the age of 40 by intractable heart failure; the second one carrying the mutation 265C>T died at the age of 30, for a trmboembolic event. A classical LGMD phenotype without heart involvement was observed in the patient with the mutation 1579C>T, who died at the age of 68 years for respiratory insufficiency.


PubMed | Oncohaematology Unit, Laboratory of Medical Genetics and Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Type: | Journal: Histopathology | Year: 2017

The aims of this study were to define whether diffuse cutaneous reticulohistiocytosis could be underpinned by somatic genetic alterations and represent precursor to more aggressive forms of disease.A 59-year-old man with diffuse cutaneous reticulohistiocytosis, experienced bone marrow localisation of the disease, with associated systemic mastocytosis and acute myeloid leukaemia. Cytogenetic analyses of the bone marrow aspirate revealed the presence of a derivative chromosome giving rise to a partial trisomy of chromosome 1q and a partial monosomy of chromosome 9q. Therefore, we characterized the cutaneous lesions before and after chemotherapy using an integrative approach combining histopathology, electron microscopy, and fluorescence in situ hybridization. Histologically, the skin lesions belonged to the spectrum of diffuse cutaneous reticulohistiocytoses, as confirmed by immunohistochemistry and ultrastructural analyses. Fluorescence in situ hybridization in the skin nodules confirmed the presence of the genetic alterations previously detected in the bone marrow.Here, we provide circumstantial evidences to suggest that at least a subset of cutaneous reticulohistiocytoses harbour clonal molecular alterations. Furthermore, we confirm that these lesions have the potential to arise in the setting of concurrent haematological disorders. In this hypothesis-generating study, two possible tumorigenesis models are proposed. This article is protected by copyright. All rights reserved.


Micale L.,Laboratory of Medical Genetics | Chaignat E.,University of Lausanne | Fusco C.,Laboratory of Medical Genetics | Reymond A.,University of Lausanne | Merla G.,Laboratory of Medical Genetics
Advances in Experimental Medicine and Biology | Year: 2012

The TRIM/RBCC proteins belong to a family whom members are involved in a variety of cellular processes such as apoptosis and cell cycle regulation. These proteins are defined by the presence of a tripartite motif composed of three zinc-binding domains, a RING finger, one or two B-box motifs, a coiled-coil region and a highly variable C-terminal region. Interestingly, the preserved order of the tripartite motif from the N-to the C-terminal end of the protein and the highly conserved overall architecture of this motif throughout evolution suggest that common biochemical functions may underline their assorted cellular roles. Here we present the structure and the proposed function of each TRIM domain including the highly variable C-terminal domain. © 2012 Landes Bioscience and Springer Science+Business Media New York.

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