Showing papers by "Guy A. Rouleau published in 2011"
TL;DR: This is the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios, and observations suggest considerable variation in mutation rates within and between families.
Abstract: J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.
567 citations
TL;DR: This study sequenced the exomes of 14 schizophrenia probands and their parents to identify 15 de novo mutations (DNMs) in eight probands, which is significantly more than expected considering the previously reported DNM rate.
Abstract: Schizophrenia is a severe psychiatric disorder that profoundly affects cognitive, behavioral and emotional processes. The wide spectrum of symptoms and clinical variability in schizophrenia suggest a complex genetic etiology, which is consistent with the numerous loci thus far identified by linkage, copy number variation and association studies. Although schizophrenia heritability may be as high as ∼80%, the genes responsible for much of this heritability remain to be identified. Here we sequenced the exomes of 14 schizophrenia probands and their parents. We identified 15 de novo mutations (DNMs) in eight probands, which is significantly more than expected considering the previously reported DNM rate. In addition, 4 of the 15 identified DNMs are nonsense mutations, which is more than what is expected by chance. Our study supports the notion that DNMs may account for some of the heritability reported for schizophrenia while providing a list of genes possibly involved in disease pathogenesis.
449 citations
TL;DR: The results demonstrate that TDP-43 and hnRNP A2 are localized to stress granules (SGs), following oxidative stress, heat shock and exposure to thapsigargin, and the cellular function of T DP-43 extends beyond splicing and places it as a participant of the central cellular response to stress and an active player in RNA storage.
Abstract: TAR deoxyribonucleic acid-binding protein 43 (TDP-43) is a multifunctional protein with roles in transcription, pre-messenger ribonucleic acid (mRNA) splicing, mRNA stability and transport. TDP-43 interacts with other heterogeneous nuclear ribonucleoproteins (hnRNPs), including hnRNP A2, via its C-terminus and several hnRNP family members are involved in the cellular stress response. This relationship led us to investigate the role of TDP-43 in cellular stress. Our results demonstrate that TDP-43 and hnRNP A2 are localized to stress granules (SGs), following oxidative stress, heat shock and exposure to thapsigargin. TDP-43 contributes to both the assembly and maintenance of SGs in response to oxidative stress and differentially regulates key SGs components, including TIA-1 and G3BP. The controlled aggregation of TIA-1 is disrupted in the absence of TDP-43 resulting in slowed SG formation. In addition, TDP-43 regulates the levels of G3BP mRNA, a SG nucleating factor. The disease-associated mutation TDP-43(R361S) is a loss-of-function mutation with regards to SG formation and confers alterations in levels of G3BP and TIA-1. In contrast, a second mutation TDP-43(D169G) does not impact this pathway. Thus, mutations in TDP-43 are mechanistically divergent. Finally, the cellular function of TDP-43 extends beyond splicing and places TDP-43 as a participant of the central cellular response to stress and an active player in RNA storage.
325 citations
TL;DR: In this article, de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic nonsyndromic intellectual disability (NSID) cases, finding 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent).
Abstract: Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.
312 citations
01 Jan 2011
TL;DR: In this paper, the role of TAR deoxyribonucleic acid-binding protein 43 (TDP-43) in cellular stress response was investigated, and it was shown that TDP43 contributes to both the assembly and maintenance of SGs in response to oxidative stress and differentially regulates key SGs components, including TIA-1 and G3BP.
Abstract: TAR deoxyribonucleic acid-binding protein 43 (TDP-43) is a multifunctional protein with roles in transcription, pre-messenger ribonucleic acid (mRNA) splicing, mRNA stability and transport. TDP-43 interacts with other heterogeneous nuclear ribonucleoproteins (hnRNPs), including hnRNP A2, via its C-terminus and several hnRNP family members are involved in the cellular stress response. This relationship led us to investigate the role of TDP-43 in cellular stress. Our results demonstrate that TDP-43 and hnRNP A2 are localized to stress granules (SGs), following oxidative stress, heat shock and exposure to thapsigargin. TDP-43 contributes to both the assembly and maintenance of SGs in response to oxidative stress and differentially regulates key SGs components, including TIA-1 and G3BP. The controlled aggregation of TIA-1 is disrupted in the absence of TDP-43 resulting in slowed SG formation. In addition, TDP-43 regulates the levels of G3BP mRNA, a SG nucleating factor. The disease-associated mutation TDP-43 R361S is a loss-of-function mutation with regards to SG formation and confers alterations in levels of G3BP and TIA-1. In contrast, a second mutation TDP-43 D169G does not impact this pathway. Thus, mutations in TDP-43 are mechanistically divergent. Finally, the cellular function of TDP-43 extends beyond splicing and places TDP-43 as a participant of the central cellular response to stress and an active player in RNA storage.
287 citations
TL;DR: Test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases, and identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations.
Abstract: Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n=142; 122 males and 20 females) or SCZ (n=143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).
276 citations
TL;DR: NRXN2 disruption to the pathogenesis of ASD is linked for the first time and the involvement of NRXN1 in SCZ is strengthened, supporting the notion of a common genetic mechanism in these disorders.
Abstract: Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders.
244 citations
TL;DR: Real-time imaging with the use of biophotonic transactive response DNA-binding protein 43 transgenic mice carrying a glial fibrillary acidic protein-luciferase reporter revealed that the behavioural defects were preceded by induction of astrogliosis, a finding consistent with a role for reactive astrocytes in amyotrophic lateral sclerosis pathogenesis.
Abstract: Transactive response DNA-binding protein 43 ubiquitinated inclusions are a hallmark of amyotrophic lateral sclerosis and of frontotemporal lobar degeneration with ubiquitin-positive inclusions. Yet, mutations in TARDBP, the gene encoding these inclusions are associated with only 3% of sporadic and familial amyotrophic lateral sclerosis. Recent transgenic mouse studies have revealed a high degree of toxicity due to transactive response DNA-binding protein 43 proteins when overexpressed under the control of strong neuronal gene promoters, resulting in early paralysis and death, but without the presence of amyotrophic lateral sclerosis-like ubiquitinated transactive response DNA-binding protein 43-positive inclusions. To better mimic human amyotrophic lateral sclerosis, we generated transgenic mice that exhibit moderate and ubiquitous expression of transactive response DNA-binding protein 43 species using genomic fragments that encode wild-type human transactive response DNA-binding protein 43 or familial amyotrophic lateral sclerosis-linked mutant transactive response DNA-binding protein 43 (G348C) and (A315T). These novel transgenic mice develop many age-related pathological and biochemical changes reminiscent of human amyotrophic lateral sclerosis including ubiquitinated transactive response DNA-binding protein 43-positive inclusions, transactive response DNA-binding protein 43 cleavage fragments, intermediate filament abnormalities, axonopathy and neuroinflammation. All three transgenic mouse models (wild-type, G348C and A315T) exhibited impaired learning and memory capabilities during ageing, as well as motor dysfunction. Real-time imaging with the use of biophotonic transactive response DNA-binding protein 43 transgenic mice carrying a glial fibrillary acidic protein-luciferase reporter revealed that the behavioural defects were preceded by induction of astrogliosis, a finding consistent with a role for reactive astrocytes in amyotrophic lateral sclerosis pathogenesis. These novel transactive response DNA-binding protein 43 transgenic mice mimic several characteristics of human amyotrophic lateral sclerosis-frontotemporal lobar degeneration and they should provide valuable animal models for testing therapeutic approaches.
238 citations
Stanford University1, University of Tokyo2, University of California, San Francisco3, University of Düsseldorf4, Peking University5, University of Copenhagen6, Technische Universität München7, University of Bologna8, Charles University in Prague9, Catholic University of Korea10, Tokyo Medical University11, Innsbruck Medical University12, University of Washington13, Université de Montréal14, Louis Pasteur University15, Memorial University of Newfoundland16, Benaroya Research Institute17, Ludwig Maximilian University of Munich18, NorthShore University HealthSystem19, University of Wisconsin-Madison20, Kaiser Permanente21
TL;DR: A SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y11 gene, is identified as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.
Abstract: Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.
210 citations
TL;DR: The present results support the hypothesis that rare de novo mutations in GRIN2A or GRin2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability.
Abstract: Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function.
210 citations
TL;DR: It is demonstrated that SYN1 is a novel predisposing gene to ASDs, in addition to epilepsy, and the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both diseases is strengthened.
Abstract: Several genes predisposing to autism spectrum disorders (ASDs) with or without epilepsy have been identified, many of which are implicated in synaptic function. Here we report a Q555X mutation in synapsin 1 (SYN1), an X-linked gene encoding for a neuron-specific phosphoprotein implicated in the regulation of neurotransmitter release and synaptogenesis. This nonsense mutation was found in all affected individuals from a large French-Canadian family segregating epilepsy and ASDs. Additional mutations in SYN1 (A51G, A550T and T567A) were found in 1.0 and 3.5% of French-Canadian individuals with autism and epilepsy, respectively. The majority of these SYN1 mutations were clustered in the proline-rich D-domain which is substrate of multiple protein kinases. When expressed in synapsin I (SynI) knockout (KO) neurons, all the D-domain mutants failed in rescuing the impairment in the size and trafficking of synaptic vesicle pools, whereas the wild-type human SynI fully reverted the KO phenotype. Moreover, the nonsense Q555X mutation had a dramatic impact on phosphorylation by MAPK/Erk and neurite outgrowth, whereas the missense A550T and T567A mutants displayed impaired targeting to nerve terminals. These results demonstrate that SYN1 is a novel predisposing gene to ASDs, in addition to epilepsy, and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both diseases.
TL;DR: TARDBP and FUS act in a pathogenic pathway that is independent of SOD1, suggesting that TARDBP acts upstream of FUS in this pathway.
Abstract: Mutations in the SOD1 and TARDBP genes have been commonly identified in Amyotrophic Lateral Sclerosis (ALS). Recently, mutations in the Fused in sarcoma gene (FUS) were identified in familial (FALS) ALS cases and sporadic (SALS) patients. Similarly to TDP-43 (coded by TARDBP gene), FUS is an RNA binding protein. Using the zebrafish (Danio rerio), we examined the consequences of expressing human wild-type (WT) FUS and three ALS–related mutations, as well as their interactions with TARDBP and SOD1. Knockdown of zebrafish Fus yielded a motor phenotype that could be rescued upon co-expression of wild-type human FUS. In contrast, the two most frequent ALS–related FUS mutations, R521H and R521C, unlike S57Δ, failed to rescue the knockdown phenotype, indicating loss of function. The R521H mutation caused a toxic gain of function when expressed alone, similar to the phenotype observed upon knockdown of zebrafish Fus. This phenotype was not aggravated by co-expression of both mutant human TARDBP (G348C) and FUS (R521H) or by knockdown of both zebrafish Tardbp and Fus, consistent with a common pathogenic mechanism. We also observed that WT FUS rescued the Tardbp knockdown phenotype, but not vice versa, suggesting that TARDBP acts upstream of FUS in this pathway. In addition we observed that WT SOD1 failed to rescue the phenotype observed upon overexpression of mutant TARDBP or FUS or upon knockdown of Tardbp or Fus; similarly, WT TARDBP or FUS also failed to rescue the phenotype induced by mutant SOD1 (G93A). Finally, overexpression of mutant SOD1 exacerbated the motor phenotype caused by overexpression of mutant FUS. Together our results indicate that TARDBP and FUS act in a pathogenic pathway that is independent of SOD1.
TL;DR: It is found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon and is a rare cause of HSANII, highlighting the potential biological relevance of alternative splicing in the peripheral sensory nervous system.
Abstract: Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal-recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system.
Technische Universität München1, Max Planck Society2, University of Turku3, Innsbruck Medical University4, University of Münster5, University of Marburg6, University of Göttingen7, Université de Montréal8, Charité9, Charles University in Prague10, University of British Columbia11, Johns Hopkins University12, Baylor College of Medicine13, Medical University of Vienna14, National Institute for Health and Welfare15, University of Helsinki16, French Institute of Health and Medical Research17, Centre national de la recherche scientifique18, Academy of Sciences of the Czech Republic19, University of Wisconsin-Madison20, Stanford University21, Ludwig Maximilian University of Munich22
TL;DR: Six RLS susceptibility loci of genome-wide significance are identified, two of them novel: an intergenic region on chromosome 2p14 (rs6747972), and a locus on 16q12.1 (rs3104767), a linkage disequilibrium block of 140 kb containing the 5′-end of TOX3 and the adjacent non-coding RNA BC034767.
Abstract: Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.
TL;DR: Evidence is provided that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism, as well as in control subjects.
TL;DR: The structure and function of β1B are studied and a novel human SCN1B epilepsy-related mutation (p.G257R) unique to β1 B is investigated, which is proposed to contribute to epilepsy through a mechanism that includes intracellular retention resulting in aberrant neuronal pathfinding.
Abstract: Scn1b-null mice have a severe neurological and cardiac phenotype. Human mutations in SCN1B result in epilepsy and cardiac arrhythmia. SCN1B is expressed as two developmentally regulated splice variants, β1 and β1B, that are each expressed in brain and heart in rodents and humans. Here, we studied the structure and function of β1B and investigated a novel human SCN1B epilepsy-related mutation (p.G257R) unique to β1B. We show that wild-type β1B is not a transmembrane protein, but a soluble protein expressed predominantly during embryonic development that promotes neurite outgrowth. Association of β1B with voltage-gated Na+ channels Nav1.1 or Nav1.3 is not detectable by immunoprecipitation and β1B does not affect Nav1.3 cell surface expression as measured by [3H]saxitoxin binding. However, β1B coexpression results in subtle alteration of Nav1.3 currents in transfected cells, suggesting that β1B may modulate Na+ current in brain. Similar to the previously characterized p.R125C mutation, p.G257R results in intracellular retention of β1B, generating a functional null allele. In contrast, two other SCN1B mutations associated with epilepsy, p.C121W and p.R85H, are expressed at the cell surface. We propose that β1B p.G257R may contribute to epilepsy through a mechanism that includes intracellular retention resulting in aberrant neuronal pathfinding.
TL;DR: A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders is identified.
Abstract: A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders
TL;DR: Findings support ATXN2 high-length repeats as a risk factor for ALS and further indicate a genetic link between spinocerebellar ataxia type 2 and ALS.
Abstract: Objective To analyze the ataxin 2 ( ATXN2 ) CAG repeat size in a cohort of patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Large (CAG) n alleles of the ATXN2 gene (27-33 repeats) were recently reported to be associated with an increased risk of ALS. Design Case-control study. Setting France and Quebec, Canada. Participants A total of 556 case patients with ALS and 471 healthy controls; both groups of participants are of French or French-Canadian origin. Results We observed a significant association between ATXN2 high-length alleles (≥29 CAG repeats) and ALS in French and French-Canadian ALS populations. Furthermore, we identified spinocerebellar ataxia type 2–pathogenic polyglutamine expansions (≥32 CAG repeats) in both familial and sporadic ALS cases. Conclusions Altogether, our findings support ATXN2 high-length repeats as a risk factor for ALS and further indicate a genetic link between spinocerebellar ataxia type 2 and ALS.
TL;DR: This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies and supports the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders.
Abstract: Deep resequencing of functional regions in human genomes is key to identifying potentially causal rare variants for complex disorders Here, we present the results from a large-sample resequencing (n = 285 patients) study of candidate genes coupled with population genetics and statistical methods to identify rare variants associated with Autism Spectrum Disorder and Schizophrenia Three genes, MAP1A, GRIN2B, and CACNA1F, were consistently identified by different methods as having significant excess of rare missense mutations in either one or both disease cohorts In a broader context, we also found that the overall site frequency spectrum of variation in these cases is best explained by population models of both selection and complex demography rather than neutral models or models accounting for complex demography alone Mutations in the three disease-associated genes explained much of the difference in the overall site frequency spectrum among the cases versus controls This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies Additionally, our findings support the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders
TL;DR: It is shown that RNA interference treatment of the MEIS1 worm orthologue increases ferritin expression in Caenorhabditis elegans and that the RLS‐associated haplotype leads to increased expression offerritin and DMT1 in RLS brain tissues.
Abstract: Restless legs syndrome (RLS) is a frequent sleep disorder that is linked to disturbed iron homeostasis. Genetic studies identified MEIS1 as an RLS-predisposing gene, where the RLS risk haplotype is associated with decreased MEIS1 mRNA and protein expression. We show here that RNA interference treatment of the MEIS1 worm orthologue increases ferritin expression in Caenorhabditis elegans and that the RLS-associated haplotype leads to increased expression of ferritin and DMT1 in RLS brain tissues. Additionally, human cells cultured under iron-deficient conditions show reduced MEIS1 expression. Our data establish a link between the RLS MEIS1 gene and iron metabolism.
TL;DR: This is the first report of a patient with a truncating mutation in STxBP1 that does not show epilepsy, thus, expanding the clinical spectrum associated with STXBP1 disruption.
Abstract: STXBP1 (Munc18-1) is a component of the machinery involved in the fusion of secretory vesicles to the presynaptic membrane for the release of neurotransmitters. De novo missense mutations in STXBP1 were recently reported in patients with Ohtahara syndrome, a form of encephalopathy with severe early-onset epilepsy. In addition, sequencing of the coding region of STXBP1 in 95 patients with non-syndromic intellectual disability (NSID) revealed de novo truncating mutations in two patients who also showed severe non-specific epilepsy, suggesting that STXBP1 disruption has the potential of causing a wide spectrum of epileptic disorders in association with intellectual disability. Here, we report on the mutational screening of STXBP1 in a different series of 50 patients with NSID and the identification of a novel de novo truncating mutation (c.1206delT/ p.Y402X) in a male with NSID, but surprisingly with no history of epilepsy. This is the first report of a patient with a truncating mutation in STXBP1 that does not show epilepsy, thus, expanding the clinical spectrum associated with STXBP1 disruption.
TL;DR: The ATG haplotype is functional and contributes to ACEi‐angioedema through a reduction in APP, and over expression of HNF4 increased the activation of haplotype ATG compared with haplotype CGG.
Abstract: Angiotensin I-converting enzyme inhibitors (ACEi) are widely used antihypertensive agents that are associated with a potentially life-threatening reaction, ACEi-angioedema. Impaired metabolism of bradykinin and des-Arg(9) -bradykinin by aminopeptidase P (APP) is a key contributor to ACEi-angioedema. This study aimed to characterize the genetic regulation of the XPNPEP2 gene and identify the genetic factors contributing to variance in plasma APP activity and ACEi-angioedema. Additive genetic factors accounted for 47.3% of variance in plasma APP activity in healthy individuals. Nested deletion analysis identified the minimal promoter (-338 bp to -147 bp) and an enhancer region (-2,502 bp to -2,238 bp). Three polymorphisms (c.-2399C>A, c.-1612G>T, and c.-393G>A) were significantly associated with plasma APP activity. Haplotype ATG was significantly associated with reduced reporter gene activity and with reduced plasma APP activity. The c.-2399C>A polymorphism was located in an enhancer region and was predicted to differentially bind hepatic nuclear factor 4 (HNF4). Over expression of HNF4 increased the activation of haplotype ATG compared with haplotype CGG. In a case control study of subjects with a history of ACEi-angioedema, haplotype ATG was significantly associated with ACEi-angioedema (OR 4.87 [1.78-13.35] P = 0.002). The ATG haplotype is functional and contributes to ACEi-angioedema through a reduction in APP.
TL;DR: Evaluating the frequency of OPTN mutations in a sample of familial and sporadic ALS cohorts found two variants were newly identified in 2 individual FALS cases and were not identified in any SALS patients, all of European descent.
TL;DR: Using a multifaceted approach based on the functional prediction of missense variants, the conservation of the altered amino acid, and the cosegregation of the variants identified in familial cases, several promising novel genes for ALS such as LUM and CRYM are identified.
Abstract: Design, Setting, and Patients: We carried out a systematic mutation screening of the entire coding regions of 29 candidate genes encoding critically important proteins for proper differentiation and development of corticospinal motor neurons in 190 patients with familial and sporadic ALS. Main Outcome Measures: We focused our analysis oncodingvariantsandevaluatedthedistributionofnonsynonymous and synonymous variants in our cohort of patients with ALS. Results: We identified 40 novel nonsynonymous variants and showed a significant excess of unique nonsynonymousvariantsinourcohortofpatientswithALS,which suggests the presence of ALS-predisposing mutations. Conclusions:Usingamultifacetedapproachbasedonthe functionalpredictionofmissensevariants,theconservation ofthealteredaminoacid,andthecosegregationofthevariantsidentifiedinfamilialcases,weidentifiedseveralpromisingnovelgenesforALSsuchasLUMandCRYM.Wehave alsohighlightedtheanalyticalchallengesoflarge-scalese
TL;DR: A review will elaborate on the possible role of the TRESK channel in regulating neuronal excitability, its role in migraine pathogenesis, and on promising therapeutic opportunities targeting this channel.
TL;DR: The findings demonstrate that different results are obtained with different platforms and illustrate the trade-off that exists between sensitivity and specificity, and supports the need for validating clinically important findings with a different technology.
Abstract: Clinical laboratories are adopting array genomic hybridization as a standard clinical test. A number of whole genome array genomic hybridization platforms are available, but little is known about their comparative performance in a clinical context. We studied 30 children with idiopathic MR and both unaffected parents of each child using Affymetrix 500 K GeneChip SNP arrays, Agilent Human Genome 244 K oligonucleotide arrays and NimbleGen 385 K Whole-Genome oligonucleotide arrays. We also determined whether CNVs called on these platforms were detected by Illumina Hap550 beadchips or SMRT 32 K BAC whole genome tiling arrays and tested 15 of the 30 trios on Affymetrix 6.0 SNP arrays. The Affymetrix 500 K, Agilent and NimbleGen platforms identified 3061 autosomal and 117 X chromosomal CNVs in the 30 trios. 147 of these CNVs appeared to be de novo, but only 34 (22%) were found on more than one platform. Performing genotype-phenotype correlations, we identified 7 most likely pathogenic and 2 possibly pathogenic CNVs for MR. All 9 of these putatively pathogenic CNVs were detected by the Affymetrix 500 K, Agilent, NimbleGen and the Illumina arrays, and 5 were found by the SMRT BAC array. Both putatively pathogenic CNVs identified in the 15 trios tested with the Affymetrix 6.0 were identified by this platform. Our findings demonstrate that different results are obtained with different platforms and illustrate the trade-off that exists between sensitivity and specificity. The large number of apparently false positive CNV calls on each of the platforms supports the need for validating clinically important findings with a different technology.
TL;DR: FUS gene mutations are rare in SALS, with four new FUS variants identified in five different SALS cases, two of which are located in the carboxy terminal of the protein where the previously reported variants were mostly clustered.
Abstract: Mutations in the FUS gene have been recently associated with amyotrophic lateral sclerosis (ALS). While most of the variants have been identified in patients with a family history of the disease, a few mutations were also found in sporadic patients. Considering this, we wanted to evaluate the frequency of mutations in the coding region of the FUS gene in a sporadic ALS (SALS) cohort compared to a control population. We tested 475 SALS cases of European origin and 475 matched controls for coding variations in the 15 exons of the FUS gene. Rare novel variants were identified in a total of five SALS patients: one missense, one deletion, one frameshift, and one nonsense substitution. Two of the four variants are located in the carboxy terminal of the protein where the previously reported variants were mostly clustered. In conclusion, FUS gene mutations are rare in SALS, with four new FUS variants identified in five different SALS cases. These findings will help evaluate the proportion of FUS variation...
TL;DR: This work has identified a putative pathogenic mutation in the gene encoding ring-finger protein RNF170, a potential ubiquitin ligase, and confirmed that the mutation dominantly disrupts normal embryonic development in zebrafish embryos.
Abstract: Autosomal dominant sensory ataxia is a rare genetic condition that results in a progressive ataxia that is caused by degeneration of the posterior columns of the spinal cord To date only two families have been clinically ascertained with this condition, both from Maritime Canada We previously mapped both families to chromosome 8p12-8q12 and have now screened the majority of annotated protein-coding genes in the shared haplotype region by direct DNA sequencing We have identified a putative pathogenic mutation in the gene encoding ring-finger protein RNF170, a potential ubiquitin ligase This mutation is a rare non-synonymous change in a well-conserved residue and is predicted to be pathogenic by SIFT, PolyPhen, PANTHER and Align-GVD Microinjection of wild-type or mutant orthologous messenger RNAs into zebrafish (Danio rerio) embryos confirmed that the mutation dominantly disrupts normal embryonic development Together these results suggest that the mutation in RNF170 is causal for the sensory ataxia in these families
TL;DR: This review aims at summarizing data from recent DNA microarray and target gene/region resequencing in order to propose new insights of where to look next in the hunt for genetic variants that would explain the majority of the missing heritability of schizophrenia.
TL;DR: It is shown that KCC3 is mainly expressed in neurons, including a subpopulation of interneurons, and that some non-neuronal cells, such as radial glial-like cells in the spinal cord, also express K CC3.