Sant'Ambrogio di Torino, Italy
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Mishra S.K.,Molecular Genetics Unit | Tisel S.M.,Molecular Genetics Unit | Orestes P.,Molecular Genetics Unit | Bhangoo S.K.,Molecular Genetics Unit | Hoon M.A.,Molecular Genetics Unit
EMBO Journal | Year: 2011

The ion-channel TRPV1 is believed to be a major sensor of noxious heat, but surprisingly animals lacking TRPV1 still display marked responses to elevated temperature. In this study, we explored the role of TRPV1-expressing neurons in somatosensation by generating mice wherein this lineage of cells was selectively labelled or ablated. Our data show that TRPV1 is an embryonic marker of many nociceptors including all TRPV1- and TRPM8-neurons as well as many Mrg-expressing neurons. Mutant mice lacking these cells are completely insensitive to hot or cold but in marked contrast retain normal touch and mechanical pain sensation. These animals also exhibit defective body temperature control and lose both itch and pain reactions to potent chemical mediators. Together with previous cell ablation studies, our results define and delimit the roles of TRPV1- and TRPM8-neurons in thermosensation, thermoregulation and nociception, thus significantly extending the concept of labelled lines in somatosensory coding. © 2011 European Molecular Biology Organization | All Rights Reserved.


Cistaro A.,Positron | Pagani M.,CNR Institute of Neuroscience | Pagani M.,Karolinska University Hospital | Montuschi A.,University of Turin | And 14 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2014

Purpose: Recently, a GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene, located on chromosome 9p21 has been demonstrated to be the commonest cause of familial amyotrophic lateral sclerosis (ALS) and to account for 5 to 10 % of apparently sporadic ALS. Relatively little is known about the brain metabolism profile of patients carrying the expansion. Our aim was to identify the [ 18F]FDG PET profile in ALS patients with the C9ORF72 expansion (C9ORF72-ALS). Methods: Fifteen C9ORF72-ALS patients were compared with 12 patients with ALS and comorbid frontotemporal dementia (FTD) without the C9ORF72 expansion (ALS-FTD) and 30 cognitively normal patients with ALS without mutations of ALS-related genes (sALS). The three groups were then cross-matched to 40 neurologically normal controls. All patients underwent FDG PET within 4 months of diagnosis. Results: The C9ORF72-ALS patients compared with the sALS patients showed significant hypometabolism in the anterior and posterior cingulate cortex, insula, caudate and thalamus, the left frontal and superior temporal cortex, and hypermetabolism in the midbrain, bilateral occipital cortex, globus pallidus and left inferior temporal cortex. The ALS-FTD patients compared with the sALS patients showed more limited hypometabolic areas, including the orbitofrontal, prefrontal, anterior cingulate and insular cortex, and hypermetabolic areas, including the bilateral occipital cortex, the left precentral and postcentral cortex and superior temporal gyrus. The C9ORF72-ALS patients compared with the ALS-FTD patients showed hypometabolism in the left temporal cortex. Conclusion: ALS patients with the C9ORF72 hexanucleotide repeat expansion had a more widespread central nervous system involvement than ALS patients without genetic mutations, with or without comorbid FTD, consistent with their more severe clinical picture. © 2014 Springer-Verlag Berlin Heidelberg.


Keller M.F.,U.S. National Institute on Aging | Keller M.F.,Temple University | Ferrucci L.,U.S. National Institute on Aging | Singleton A.B.,U.S. National Institute on Aging | And 6 more authors.
JAMA Neurology | Year: 2014

IMPORTANCE: Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations. OBJECTIVE: To estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies. DESIGN, SETTING, AND PARTICIPANTS: We applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets thatwere generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypeswebsite (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland. MAIN OUTCOMES AND MEASURES: A linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability. RESULTS: With our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk. CONCLUSIONS AND RELEVANCE: We found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesizemay contain causative risk variants that influence susceptibility to ALS. Copyright 2014 American Medical Association. All rights reserved.


Borras E.,Molecular Genetics Unit | de Sousa Dias M.,Molecular Genetics Unit | Hernan I.,Molecular Genetics Unit | Pascual B.,Molecular Genetics Unit | And 4 more authors.
Clinical Genetics | Year: 2013

We explored an approach to detect disease-causing sequence variants in 448 candidate genes from five index cases of autosomal dominant retinitis pigmentosa (adRP) by sequence DNA capture and next-generation DNA sequencing (NGS). Detection of sequence variants was carried out by sequence capture NimbleGen and NGS in a SOLiD platform. After filtering out variants previously reported in genomic databases, novel potential adRP-causing variants were validated by dideoxy capillary electrophoresis (Sanger) sequencing and co-segregation in the families. A total of 55 novel sequence variants in the coding or splicing regions of adRP candidate genes were detected, 49 of which were confirmed by Sanger sequencing. Segregation of these variants in the corresponding adRP families showed three variants present in all the RP-affected members of the family. A novel mutation, p.L270R in IMPDH1, was found to be disease causing in one family. In another family a variant, p.M96T in the NRL gene was detected; this variant was previously reported as probably causing adRP. However, the previously reported p.A76V mutation in NRL as a cause of RP was excluded by co-segregation in the family. We discuss the benefits and limitations of our approach in the context of mutation detection in adRP patients. © 2013 John Wiley & Sons A/S.


Akawi N.A.,United Arab Emirates University | Canpolat F.E.,Zekai Tahir Burak Maternity Hospital | White S.M.,Murdoch Childrens Research Institute | White S.M.,University of Melbourne | And 7 more authors.
Human Mutation | Year: 2013

We have recently shown that the hemorrhagic destruction of the brain, subependymal, calcification, and congenital cataracts is caused by biallelic mutations in the gene encoding junctional adhesion molecule 3 (JAM3) protein. Affected members from three new families underwent detailed clinical examination including imaging of the brain. Affected individuals presented with a distinctive phenotype comprising hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. All patients had a catastrophic clinical course resulting in death. Sequencing the coding exons of JAM3 revealed three novel homozygous mutations: c.2T>G (p.M1R), c.346G>A (p.E116K), and c.656G>A (p.C219Y). The p.M1R mutation affects the start codon and therefore is predicted to impair protein synthesis. Cellular studies showed that the p.C219Y mutation resulted in a significant retention of the mutated protein in the endoplasmic reticulum, suggesting a trafficking defect. The p.E116K mutant traffics normally to the plasma membrane as the wild-type and may have lost its function due to the lack of interaction with an interacting partner. Our data further support the importance of JAM3 in the development and function of the vascular system and the brain. © 2012 Wiley Periodicals, Inc.


Chio A.,University of Turin | Battistini S.,University of Siena | Calvo A.,University of Turin | Caponnetto C.,University of Genoa | And 14 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2014

The clinical approach to patients with amyotrophic lateral sclerosis (ALS) has been largely modified by the identification of novel genes, the detection of gene mutations in apparently sporadic patients, and the discovery of the strict genetic and clinical relation between ALS and frontotemporal dementia (FTD). As a consequence, clinicians are increasingly facing the dilemma on how to handle genetic counselling and testing both for ALS patients and their relatives. On the basis of existing literature on genetics of ALS and of other late-onset life-threatening disorders, we propose clinical suggestions to enable neurologists to provide optimal clinical and genetic counselling to patients and families. Genetic testing should be offered to ALS patients who have a first-degree or second-degree relative with ALS, FTD or both, and should be discussed with, but not offered to, all other ALS patients, with special emphasis on its major uncertainties. Presently, genetic testing should not be proposed to asymptomatic at-risk subjects, unless they request it or are enrolled in research programmes. Genetic counselling in ALS should take into account the uncertainties about the pathogenicity and penetrance of some genetic mutations; the possible presence of mutations of different genes in the same individual; the poor genotypic/phenotypic correlation in most ALS genes; and the phenotypic pleiotropy of some genes. Though psychological, social and ethical implications of genetic testing are still relatively unexplored in ALS, we recommend multidisciplinary counselling that addresses all relevant issues, including disclosure of tests results to family members and the risk for genetic discrimination.


Catena N.,G Gaslini Institute | Divizia M.T.,Molecular Genetics Unit | Calevo M.G.,Epidemiology and Biostatistics Section | Baban A.,Molecular Genetics Unit | And 4 more authors.
Journal of Pediatric Orthopaedics | Year: 2012

BACKGROUND: The Poland anomaly (PA) comprises unilateral absence or hypoplasia of the pectoralis major muscle and a variable degree of ipsilateral hand and upper limb anomalies. Various hand and upper limb anomalies classifications in PA have been previously published. In this work, a new classification of hand and upper limb anomalies in PA is proposed, on the basis of the clinical and instrumental evaluation of 175 patients. METHODS: The patients have been followed by a multidisciplinary approach, consisting in orthopaedic, surgical, and genetic evaluation and chest, upper limb, and ultrasound examination of major and minor pectoralis muscles, heart, and kidney. RESULTS: Hand and upper limb anomalies were classified in 8 groups on the basis of the clinical degree of severity and on the basis of the presence of coexisting associated anomalies. Data regarding the sex and laterality, previously reported in the medical literature, were confirmed by our analysis. Etiopathogenetic mechanisms leading to the anomaly are discussed. CONCLUSIONS: The proposed classification is derived from the observation of the widest group of patients described in the medical literature. Our proposal could help in the management of patients affected by Poland syndrome and in understanding etiological and pathologic aspects of the disease. LEVEL OF EVIDENCE: IV. Copyright © 2012 by Lippincott Williams & Wilkins.


PubMed | APHP Hopital Necker Enfants Malades, University of Paris Descartes and Molecular Genetics Unit
Type: | Journal: BMC psychiatry | Year: 2015

Deletions and mutations involving the SHANK3 gene lead to a nonspecific clinical presentation with moderate to profound intellectual disability, severely delayed or absent speech, and autism spectrum disorders (ASD). Better knowledge of the clinical spectrum of SHANK3 haploinsufficiency is useful to facilitate clinical care monitoring and to guide molecular diagnosis, essential for genetic counselling.Here, we report a detailed clinical description of a 10-year-old girl carrying a pathogenic interstitial 22q13.3 deletion encompassing only the first 17 exons of SHANK3. The clinical features displayed by the girl strongly suggested the diagnosis of dementia infantilis, described by Heller in 1908, also known as childhood disintegrative disorder.Our present case confirms several observations according to which regression may be part of the clinical phenotype of SHANK3 haploinsufficiency. Therefore, we think it is crucial to look for mutations in the gene SHANK3 in patients diagnosed for childhood disintegrative disorder or any developmental disorder with a regressive pattern involving social and communicative skills as well as cognitive and instinctual functions, with onset around 3 years.


PubMed | U.S. National Institute on Aging, University of Turin, Temple University, Molecular Genetics Unit and 2 more.
Type: Journal Article | Journal: JAMA neurology | Year: 2014

Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.To estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies.We applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle dAosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland.A linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability.With our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk.We found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS.


PubMed | University of Turin, University of Kansas Medical Center, Illinois College, University of Miami and 16 more.
Type: Journal Article | Journal: JAMA neurology | Year: 2015

Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood.To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study.DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication.We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.010(-8) was set for genome-wide significance after Bonferroni correction for multiple testing.In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.9810(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.0810(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.6010(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.3210(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.0210(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.5210(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases.Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

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