Genome-wide expression profiling and functional characterization of SCA28 lymphoblastoid cell lines reveal impairment in cell growth and activation of apoptotic pathways

BACKGROUND: SCA28 is an autosomal dominant ataxia associated with AFG3L2 gene mutations. We performed a whole genome expression profiling using lymphoblastoid cell lines (LCLs) from four SCA28 patients and six unrelated healthy controls matched for sex and age. METHODS: Gene expression was evaluated with the Affymetrix GeneChip Human Genome U133A 2.0 Arrays and data were validated by real-time PCR. RESULTS: We found 66 genes whose expression was statistically different in SCA28 LCLs, 35 of which were up-regulated and 31 down-regulated. The differentially expressed genes were clustered in five functional categories: (1) regulation of cell proliferation; (2) regulation of programmed cell death; (3) response to oxidative stress; (4) cell adhesion, and (5) chemical homeostasis. To validate these data, we performed functional experiments that proved an impaired SCA28 LCLs growth compared to controls (p\u2009<\u20090.005), an increased number of cells in the G0/G1 phase (p\u2009<\u20090.001), and an increased mortality because of apoptosis (p\u2009<\u20090.05). We also showed that respiratory chain activity and reactive oxygen species levels was not altered, although lipid peroxidation in SCA28 LCLs was increased in basal conditions (p\u2009<\u20090.05). We did not detect mitochondrial DNA large deletions. An increase of TFAM, a crucial protein for mtDNA maintenance, and of DRP1, a key regulator of mitochondrial dynamic mechanism, suggested an alteration of fission/fusion pathways. CONCLUSIONS: Whole genome expression profiling, performed on SCA28 LCLs, allowed us to identify five altered functional categories that characterize the SCA28 LCLs phenotype, the first reported in human cells to our knowledge. \ua9 2013 Mancini et al.; licensee BioMed Central Ltd

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Comprendre les mots du cancer : LexOnco, dictionnaire d'oncologie pour les personnes malades et leurs proches. Aspects méthodologiques

International audienceIn response to the evolution of the information-seeking behaviour of patients and concerns from health professionals regarding cancer patient information, nthe French National Federation of Comprehensive Cancer Centres (FNCLCC) introduced, in 1998, an information and education program dedicated to patients and relatives, the SOR SAVOIR PATIENT program. Lexonco project is a dictionary on oncology adapted for patients and relatives and validated by medical experts and cancer patients. This paper describes the methodological aspects which take into account patients and experts'perspectives to produce the definitions.Face à l'augmentation de la demande d'information des personnes malades et à leur rôle croissant dans la prise de décision médicale, l'accès à une information validée, compréhensible et systématiquement actualisée, en correspondance avec leurs besoins, est un enjeu majeur de Santé publique. Améliorer la qualité de la prise en charge des patients passe par l'appropriation des principaux termes en lien avec la maladie. Dans le cadre du programme pluridisciplinaire SOR SAVOIR PATIENT, le projet Lexonco (LEXique d'ONCOlogie) vise à offrir aux patients un dictionnaire sur le cancer, validé sur le plan médical et qui tient compte des besoins d'information et des préférences des personnes concernées par le cancer. Cet article décrit le projet en insistant plus particulièrement sur les principaux aspects méthodologiques mis en œuvre pour construire et valider les définitions destinées aux patients

Les SOR SAVOIR PATIENT, un programme d'information et d'éducation des patients atteints de cancer et de leurs proches

Afin de répondre aux besoins des patients et aux préoccupations des professionnels de santé, la Fédération nationale des centres de lutte contre le cancer (FNCLCC) et les 20 Centres régionaux de lutte contre le cancer (CRLCC) ont mis en place, depuis 1998, les SOR SAVOIR PATIENT. Ce programme vise à mettre à la disposition des patients atteints de cancer et de leurs proches une information validée, compréhensible, accessible et régulièrement actualisée sur les différents cancers et leurs traitements et à offrir aux médecins une base d'informations synthétiques et compréhensibles en vue d'une meilleure prise en charge des patients venant les consulter. La loi n° 2002-303 du 4 mars relative aux droits des malades et à la qualité du système de santé et l'évolution de l'organisation des soins en cancérologie (plan Cancer 2003) confèrent une importance particulière à l'information des patients. La reconnaissance du droit à l'information du patient et l'accès direct au dossier médical contribuent notamment aux modifications des liens entre les médecins et les patients. La personne malade ne peut plus être regardée comme passive et soumise aux décisions médicales. La mise à disposition d'informations de qualité, actualisées, compréhensibles et répondant aux besoins des personnes concernées par le cancer constitue ainsi un enjeu majeur de santé publique et une priorité nationale et européenne

Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes

Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases. © The Author (2014).SCOPUS: ar.jinfo:eu-repo/semantics/publishe