Identification, par criblage génomique à haut débit, de Variations du Nombre de Copies impliquées dans les formes précoces de Maladie d'Alzheimer

L’étude des formes rares de maladie d’Alzheimer (MA) s’est avérée être une stratégie utile dans l’identification de gènes impliqués dans le déterminisme de la MA. Cette stratégie a permis d’identifier les mutations des gènes APP, PSEN1 et PSEN2 dans 77% des formes autosomiques dominantes à début précoce de MA (ADEOAD). Les variations du nombre de copies (CNVs) sont définies comme « des segments d’ADN d’au moins 1 kb pour lesquels des différences du nombre de copies ont été identifiées par comparaison entre deux génomes ». On estime à ce jour que plus de 30% des gènes sont soumis à des CNVs, et qu’un individu sur 10 porte un CNV de novo. Dans ce cadre, nous avons émis l’hypothèse que des variations du nombre de copies (CNVs) rares pouvaient être à l’origine de la pathologie chez certaines familles ADEOAD sans mutation identifiée dans les gènes connus, de même que chez des cas rares de MA sporadique à début précoce. En utilisant l’hybridation génomique comparative à haute-résolution, nous avons recherché la présence des CNVs rares chez 21 cas ADEOAD non-apparentés, sans altération sur les gènes connus, et 12 cas de MA sporadique, avec un âge de début avant 55 ans.Les analyses ont révélé la présence de 7 CNVs uniques (4 chez les ADEOAD et 3 chez les cas isolés) non retrouvés chez 1078 contrôles et 912 cas de MA à début tardif.De façon intéressante, 4 de ces 7 réarrangements touchent des gènes (KLK6, SLC30A3, MEOX2, and FPR2) codant des protéines fortement associées aux voies métaboliques et de signalisation du peptide β-amyloïde.Bien que ces CNVs soient des variants individuels rares et associés à des sous-groupes particuliers de patients, ces résultats renforcent le rôle causal, dans la MA, d’un groupe de gènes codant des molécules suspectées de longue date, de modifier le métabolisme ou la signalisation de l’Aβ, et pour lesquels des modèles animaux ou cellulaires ont déjà été développés

Identification, par criblage génomique à haut débit, de Variations du Nombre de Copies impliquées dans les formes précoces de Maladie d'Alzheimer

L’étude des formes rares de maladie d’Alzheimer (MA) s’est avérée être une stratégie utile dans l’identification de gènes impliqués dans le déterminisme de la MA. Cette stratégie a permis d’identifier les mutations des gènes APP, PSEN1 et PSEN2 dans 77% des formes autosomiques dominantes à début précoce de MA (ADEOAD). Les variations du nombre de copies (CNVs) sont définies comme « des segments d’ADN d’au moins 1 kb pour lesquels des différences du nombre de copies ont été identifiées par comparaison entre deux génomes ». On estime à ce jour que plus de 30% des gènes sont soumis à des CNVs, et qu’un individu sur 10 porte un CNV de novo. Dans ce cadre, nous avons émis l’hypothèse que des variations du nombre de copies (CNVs) rares pouvaient être à l’origine de la pathologie chez certaines familles ADEOAD sans mutation identifiée dans les gènes connus, de même que chez des cas rares de MA sporadique à début précoce. En utilisant l’hybridation génomique comparative à haute-résolution, nous avons recherché la présence des CNVs rares chez 21 cas ADEOAD non-apparentés, sans altération sur les gènes connus, et 12 cas de MA sporadique, avec un âge de début avant 55 ans.Les analyses ont révélé la présence de 7 CNVs uniques (4 chez les ADEOAD et 3 chez les cas isolés) non retrouvés chez 1078 contrôles et 912 cas de MA à début tardif.De façon intéressante, 4 de ces 7 réarrangements touchent des gènes (KLK6, SLC30A3, MEOX2, and FPR2) codant des protéines fortement associées aux voies métaboliques et de signalisation du peptide β-amyloïde.Bien que ces CNVs soient des variants individuels rares et associés à des sous-groupes particuliers de patients, ces résultats renforcent le rôle causal, dans la MA, d’un groupe de gènes codant des molécules suspectées de longue date, de modifier le métabolisme ou la signalisation de l’Aβ, et pour lesquels des modèles animaux ou cellulaires ont déjà été développés

TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration.

International audienceTDP-43 (TAR-DNA binding protein) aggregates in neuronal inclusions in motoneuron disease (MND), as well as in frontotemporal lobar degeneration (FTLD) and FTLD associated with MND (FTLD-MND). Mutations in TARDBP gene, coding for TDP-43, were found in patients with pure MND. We now describe TARDBP mutations in two patients with FTLD-MND, presenting with a behavioral variant of FTLD and semantic dementia, suggesting that TDP-43 may also have a direct pathogenic role in FTLD disorders

Type I hyperprolinemia: genotype/phenotype correlations.

Type I hyperprolinemia (HPI) is an autosomal recessive disorder associated with cognitive and psychiatric troubles, caused by alterations of the Proline Dehydrogenase gene (PRODH) at 22q11. HPI results from PRODH deletion and/or missense mutations reducing proline oxidase (POX) activity. The goals of this study were first to measure in controls the frequency of PRODH variations described in HPI patients, second to assess the functional effect of PRODH mutations on POX activity, and finally to establish genotype/enzymatic activity correlations in a new series of HPI patients. Eight of 14 variants occurred at polymorphic frequency in 114 controls. POX activity was determined for six novel mutations and two haplotypes. The c.1331G>A, p.G444D allele has a drastic effect, whereas the c.23C>T, p.P8L allele and the c.[56C>A; 172G>A], p.[Q19P; A58T] haplotype result in a moderate decrease in activity. Among the 19 HPI patients, 10 had a predicted residual activity or = 50% bore at least one c.824C>A, p.T275N allele, which has no detrimental effect on activity but whose frequency in controls is only 3%. Our results suggest that PRODH mutations lead to a decreased POX activity or affect other biological parameters causing hyperprolinemia

Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.

International audienceCONTEXT: Results of comparative genomic hybridization studies have suggested that rare copy number variations (CNVs) at numerous loci are involved in the cause of mental retardation, autism spectrum disorders, and schizophrenia. OBJECTIVES: To provide an estimate of the collective frequency of a set of recurrent or overlapping CNVs in 3 different groups of cases compared with healthy control subjects and to assess whether each CNV is present in more than 1 clinical category. DESIGN: Case-control study. SETTING: Academic research. PARTICIPANTS: We investigated 28 candidate loci previously identified by comparative genomic hybridization studies for gene dosage alteration in 247 cases with mental retardation, in 260 cases with autism spectrum disorders, in 236 cases with schizophrenia or schizoaffective disorder, and in 236 controls. MAIN OUTCOME MEASURES: Collective and individual frequencies of the analyzed CNVs in cases compared with controls. RESULTS: Recurrent or overlapping CNVs were found in cases at 39.3% of the selected loci. The collective frequency of CNVs at these loci is significantly increased in cases with autism, in cases with schizophrenia, and in cases with mental retardation compared with controls (P < .001, P = .01, and P = .001, respectively, Fisher exact test). Individual significance (P = .02 without correction for multiple testing) was reached for the association between autism and a 350-kilobase deletion located at 22q11 and spanning the PRODH and DGCR6 genes. CONCLUSIONS: Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs (which contain genes involved in neurotransmission or in synapse formation and maintenance) are present in the 3 pathologic conditions (schizophrenia, autism, and mental retardation), supporting the existence of shared biologic pathways in these neurodevelopmental disorders

Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome.

Microdeletions of the 22q11 region, responsible for the velo-cardio-facial syndrome (VCFS), are associated with an increased risk for psychosis and mental retardation. Recently, it has been shown in a hyperprolinemic mouse model that an interaction between two genes localized in the hemideleted region, proline dehydrogenase (PRODH) and catechol-o-methyl-transferase (COMT), could be involved in this phenotype. Here, we further characterize in eight children the molecular basis of type I hyperprolinemia (HPI), a recessive disorder resulting from reduced activity of proline dehydrogenase (POX). We show that these patients present with mental retardation, epilepsy and, in some cases, psychiatric features. We next report that, among 92 adult or adolescent VCFS subjects, a subset of patients with severe hyperprolinemia has a phenotype distinguishable from that of other VCFS patients and reminiscent of HPI. Forward stepwise multiple regression analysis selected hyperprolinemia, psychosis and COMT genotype as independent variables influencing IQ in the whole VCFS sample. An inverse correlation between plasma proline level and IQ was found. In addition, as predicted from the mouse model, hyperprolinemic VCFS subjects bearing the Met-COMT low activity allele are at risk for psychosis (OR = 2.8, 95% CI = 1.04-7.4). Finally, from the extensive analysis of the PRODH gene coding sequence variations, it is predicted that POX residual activity in the 0-30% range results into HPI, whereas residual activity in the 30-50% range is associated either with normal plasma proline levels or with mild-to-moderate hyperprolinemia.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease.

International audienceStudying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases. Using high-resolution array comparative genomic hybridisation, we assessed the presence of rare CNVs in 21 unrelated ADEOAD cases, having no alteration on known genes, and 12 sporadic AD cases, with an age of onset younger than 55 years. The analysis revealed the presence of 7 singleton CNVs (4 in ADEOAD and 3 in sporadic cases) absent in 1078 controls and 912 late-onset AD cases. Strikingly, 4 out of 7 rearrangements target genes (KLK6, SLC30A3, MEOX2, and FPR2) encoding proteins that are tightly related to amyloid-β peptide metabolism or signalling. Although these variants are individually rare and restricted to particular subgroups of patients, these findings support the causal role, in human pathology, of a set of genes coding for molecules suspected for a long time to modify Aβ metabolism or signalling, and for which animal or cellular models have already been developed

Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance