Showing papers by "Guy A. Rouleau published in 2003"

Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

Abstract: Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.

Mutations in a Gene Encoding a Novel Protein Containing a Phosphotyrosine-Binding Domain Cause Type 2 Cerebral Cavernous Malformations

Abstract: Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. Mutations in the gene KRIT1 are responsible for type 1 CCM (CCM1). We report that a novel gene, MGC4607, exhibits eight different mutations in nine families with type 2 CCM (CCM2). MGC4607, similar to the KRIT1 binding partner ICAP1α, encodes a protein with a phosphotyrosine-binding domain. This protein may be part of the complex pathway of integrin signaling that, when perturbed, causes abnormal vascular morphogenesis in the brain, leading to CCM formation.

Maternal alleles acquiring paternal methylation patterns in biparental complete hydatidiform moles

Abstract: We previously mapped a maternal locus responsible for biparental complete hydatidiform moles (BiCHMs) to 19q13.4. The two index patients had a total of 14 molar pregnancies, eight abortions at various developmental stages, and one 16-year-old healthy offspring. We suggested that the defective gene deregulates the expression of imprinted genes. Here, we report the methylation status of four imprinted genes in two BiCHMs from the two sisters, the 16-year-old normal offspring, and two sporadic BiCHMs from unrelated patients. Using two bisulfite-based methods, we demonstrate a general trend of abnormal hypomethylation at the paternally expressed genes, PEG3 and SNRPN, and hypermethylation at the maternally expressed genes, NESP55 and H19, in two to four BiCHMs. Using single nucleotide polymorphisms, we provide the first evidence that SNRPN, NESP55 and H19 are abnormally methylated on the maternal alleles in BiCHMs. We show, in the BiCHMs from the two sisters, that the abnormally methylated H19 allele is inherited from either the maternal grandmother or the maternal grandfather. These data suggest that the abnormal methylation in BiCHMs is not due to an error in erasing the parental imprinting marks but rather in the re-establishment of the new maternal marks during oogenesis or their postzygotic maintenance. The defective 19q13.4 locus may have led to the development of variable degrees of 'faulty' paternal marks on the maternal chromosomes.

Diagnosing zygosity in infant twins: physical similarity, genotyping, and chorionicity.

Abstract: We compared the results of different methods for diagnosing zygosity in a sample of 237 same-sex pairs of twins assessed at 5 and 18 months of age. Despite the twins' very young age and early stage of development, physical similarity was concordant with genotyping in 91.9% of cases at 5 months and 93.8% of cases at 18 months, for a subsample of 123 and 113 pairs, respectively. This concordance rate was obtained following a case-by-case assessment of each pair's physical similarity using a shortened version of the Zygosity Questionnaire for Young Twins (Goldsmith, 1991). Taking into account the chorionicity data available from the twins' medical files, we were able to classify correctly 96% of the pairs, an accuracy rate comparable to previously reported rates obtained with older twins. Chorionicity data is especially useful since we found that monochorionic MZ twins are more difficult than dichorionic MZ twins to diagnose by physical similarity at these young ages. The relative cost-benefit of methods based on reported physical similarity and DNA analysis is discussed in light of these results.

Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy

Abstract: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant muscular dystrophy that results from small expansions of a polyalanine tract in the PABPN1 gene. Intranuclear inclusions are the pathological hallmark of OPMD. The mechanism by which protein aggregation in OPMD might relate to a toxic gain-of-function has so far remained elusive. Whether protein aggregates themselves are pathogenic or are the consequence of an unidentified underlying molecular mechanism is still unclear. Here, we report that protein aggregation in a cell model of OPMD directly impaires the function of the ubiquitin-proteasome pathway (UPP) as well as molecular chaperone functions. The proteasome inhibitor lactacystin causes significant increase of protein aggregation and toxicity. Moreover, overexpression of molecular chaperones (HSP40 and HSP70) suppressed protein aggregation and toxicity. We also provide evidence that mPABPN1-ala17 protein aggregation proportionally correlates with toxicity. Furthermore, we show that co-expression of chaperones in our OPMD cell model increases the solubility of mPABPN1-ala17 and transfected cell survival rate. Our studies suggest that molecular regulators of polyalanine protein solubility and degradation may provide insights into new mechanisms in OPMD pathogenesis. Further analysis of the cellular and molecular mechanisms by which UPP and molecular chaperones influence the degradation of misfolded proteins could provide novel concepts and targets for the treatment and understanding of the pathogenesis of OPMD and neurodegenerative diseases.

Polymorphism, shared functions and convergent evolution of genes with sequences coding for polyalanine domains

Abstract: Mutations causing expansions of polyalanine domains are responsible for nine hereditary diseases. Other GC-rich sequences coding for some polyalanine domains were found to be polymorphic in human. These observations prompted us to identify all sequences in the human genome coding for polyalanine stretches longer than four alanines and establish their degree of polymorphism. We identified 494 annotated human proteins containing 604 polyalanine domains. Thirty-two percent (31/98) of tested sequences coding for more than seven alanines were polymorphic. The length of the polyalanine-coding sequence and its GCG or GCC repeat content are the major predictors of polymorphism. GCG codons are over-represented in human polyalanine coding sequences. Our data suggest that GCG and GCC codons play a key role in polyalanine-coding sequence appearance and polymorphism. The grouping by shared function of polyalanine-containing proteins in Homo sapiens, Drosophila melanogaster and Caenorhabditis elegans shows that the majority are involved in transcriptional regulation. Phylogenetic analyses of HOX, GATA and EVX protein families demonstrate that polyalanine domains arose independently in different members of these families, suggesting that convergent molecular evolution may have played a role. Finally polyalanine domains in vertebrates are conserved between mammals and are rarer and shorter in Gallus gallus and Danio rerio. Together our results show that the polymorphic nature of sequences coding for polyalanine domains makes them prime candidates for mutations in hereditary diseases and suggests that they have appeared in many different protein families through convergent evolution.

An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred.

Abstract: Hereditary spastic paraplegia (HSP) and amyotrophic lateral sclerosis (ALS) are genetically heterogeneous progressive neurodegenerative disorders distinguished by differential motor neuron involvement. In ALS, both upper and lower motor neurons are affected, whereas in HSP only upper motor neuron function is affected, resulting in a less severe disease. Recently, juvenile forms of ALS (ALS2) and primary lateral sclerosis (PLS) were shown to be caused by mutations in the ALS2 gene, which encodes a putative GTPase regulator. The ALS2 gene has 34 exons with at least two splice variants. The long variant (6,394 nucleotides) is expressed in various tissues with highest expression in the brain. The protein, alsin, shows similarity to three domains (RCC1, Pleckstrin-DB1, VPS9) and to membrane occupation and recognition nexus repeat motifs, which are characteristic of various guanine exchange factors (Ran, Rho, and Rab, respectively). We report the identification of a novel ALS2 mutation in a large consanguineous Pakistani kindred with infantileonset autosomal recessive complicated HSP. The proband initially presented with gait disturbance and hyperreflexia at 18 months. Currently, at age 12 years, she is anarthric and confined to a wheelchair. Family history indicates that the disease slowly progresses to tetraplegia and death by the fourth decade of life, with relatively preserved intellect. The clinical picture is similar to that recently reported by Eymard-Pierre and colleagues. Because our family is clinically related to previously reported ALS2 families and the fact that an HSP locus (SPG13) initially overlapped with the ALS2 locus, the proband was analyzed for mutations in the ALS2 gene using the denaturing high performance liquid chromatography (DHPLC)–WAVE system (Transgenomics, Mountain View, CA). Sequencing of a DHPLC variant in exon 32 showed a 1bp deletion (4844delT; Fig, a). Cosegregation of the mutation and the disease in the family was confirmed, and the mutation was absent in 155 control individuals. The deletion occurs at the beginning of the VPS9 domain and adds 43 unique residues to the truncated protein (see Fig, b). Our results show that absence of a functional VPS9 domain of alsin is sufficient to cause neurodegeneration. The yeast VPS9 protein and its mammalian homolog RABEX-5 are guanine nucleotide exchange factors for specific proteins thought to be involved in vacuolar endocytic transport. Disruption of intracellular trafficking has long been suggested to cause selective degeneration of the long axons of the pyramidal tract in HSP, but identification of additional mutations, functional studies, and animal models are necessary to further understand the pathogenesis resulting from ALS2 mutations.

Mutational analysis of 206 families with cavernous malformations

Abstract: Object. A gene contributing to the autosomal-dominant cerebral cavernous malformation (CCM) phenotype, KRIT1 (an acronym for Krev Interaction Trapped 1), has been identified through linkage analysis and mutation screening. The authors collected blood samples from 68 patients with familial CCM and 138 patients with apparently sporadic CCM as well as from their families, in an effort to characterize the prevalence and spectrum of disease-causing sequence variants in the KRIT1 gene. Methods. The authors used single-strand conformational polymorphism analysis to identify genomic variants in KRIT1, which were sequenced to determine the specific mutation. Among 43 Hispanic-American kindreds who immigrated to the southwestern US from northern Mexico, 31 share an identical founder mutation. This Q455X mutation is found in 18 (86%) of 21 persons with a positive family history and in 13 (59%) of 22 persons with apparently sporadic CCM. This mutation was not found among 13 persons with CCM who were recruited from Me...

Mutation screening of FOXP2 in individuals diagnosed with autistic disorder.

Abstract: Although it is well established that genetic factors play an important role in the etiology of autistic disorder (AD), no specific genes have as yet been implicated. Genetic epidemiological data, particularly the sharp fall in concordance rates from monozygotic to dizygotic twins, indicate that the mode of transmission of this disorder is complex and may involve several genes. The 7q31 locus has been repeatedly linked to AD, suggesting that this chromosomal region is likely to harbor a susceptibility gene for AD. Recently, variations in the FOXP2 gene were reported to be responsible for a severe speech and language disorder. Because of the chromosomal location of FOXP2 (7q31) and the putative implication of the 7q31 region both in autistic and in language disorders (a feature of AD), it has been hypothesized that FOXP2 may be implicated in the pathophysiology of AD. To test this hypothesis, we screened the FOXP2 gene coding sequence for mutations in subjects diagnosed with AD and in normal controls. We identified four silent polymorphisms that were equally distributed between patients and controls. Using an intra-family association design, we identified no transmission disequilibrium in any of the four identified alleles, suggesting that the FOXP2 gene does not play a significant role in AD.

Wolfram syndrome and suicide: Evidence for a role of WFS1 in suicidal and impulsive behavior.

Abstract: There is evidence suggesting that subjects affected with the Wolfram syndrome (WFS) and normal carriers present an increased risk of psychiatric disorders, particularly depression and suicidal behavior. We investigated a possible role of the gene involved in WFS (WFS1) in the neurobiology of suicide and the potential modulatory effect on traits associated to suicidal behavior. Genetic variation at WFS1 (H611R, R456H, and I333V) was investigated in 111 suicide victims and 129 normal controls. Possible effects on psychopathology and behavioral traits were investigated in a subsample of suicide cases (N = 31) for whom phenotyping was carried out by means of structured psychiatric interviews and questionnaires adapted for psychological autopsies. We found a significantly higher frequency of the 611R/611R genotype in suicide completers as compared to controls (χ2 = 19.21, df=2, P = 0.001). Suicide completers with this genotype had higher scores on measures of impulsivity (t = −3.15, df = 15.3, P = 0.006); novelty seeking (NS) (t = −3.35, df = 13.8, P = 0.005); and conversely, lower scores of persistence (t = 2.4, df = 16.6, P = 0.028). Scores of impulsivity and NS remained higher in subjects with the associated genotype after adjusting for age, gender, and psychopathology. These results suggest a role for WFS1 in the pathophysiology of impulsive suicide, and are consistent with previous clinical reports suggesting an increased risk of suicidal behavior in WFS homozygotes and heterozygotes. However, these findings are preliminary and should be confirmed in independent samples. © 2003 Wiley-Liss, Inc.

Dopamine beta-hydroxylase (DBH) gene and schizophrenia phenotypic variability: a genetic association study.

Abstract: Recently, two polymorphisms (DBH5′-Ins/del and DBH 444 g/a) of the Dopamine Beta Hydroxylase (DBH) gene were isolated, and one haplotype (Del-a) was found to be associated with low DBH activity and cocaine-induced paranoia. The purpose of this study is to test for association between these two polymorphisms and schizophrenia or its phenotypic variability with respect to neuroleptic therapeutic response and symptom profile. Allelic and haplotype distributions of these two polymorphisms were compared between two groups of schizophrenic patients (excellent neuroleptic-responders; R, n = 42 and non-responders; NR, n = 64), and one group of healthy volunteers (n = 120). The “Del” and “a” alleles were in positive linkage disequilibrium. No allelic or genotype differences in the distribution of these two polymorphisms were observed between patients and controls. However, The Del-a haplotype was significantly more common in NR patients, and the mean total BPRS score was significantly higher in the group of patients with the Del-a compared to those without the Del-a haplotype. These results suggest that the DBH gene is not a causative factor in schizophrenia but that it may be a modulator of psychotic symptoms, severity of the disorder and therapeutic response to neuroleptic drugs. © 2003 Wiley-Liss, Inc.

HnRNP A1 and A/B interaction with PABPN1 in oculopharyngeal muscular dystrophy.

Abstract: Interaction de hnRNP A1 et A/B avec PABPN1 dans la dystrophie musculaire oculopharyngee. Introduction: La dystrophie musculaire oculopharyngee (DMOP) est une maladie de l'âge adulte caracterisee par une ptose progressive des paupieres, une dysphagie et une faiblesse musculaire proximale. La forme autosomique dominante est causee par de courtes expansions d'une repetition (GCG)6 a (GCG)8-13 dans le gene PABPN1. Les mutations donnent lieu a une expansion d'un tractus de polyalanine de 10 a 12-17 alanines dans la partie N-terminale de PABPN1. Le gene PABPNI mute (PABPN1m) induit la formation d'inclusions filamenteuses intranucleaires qui sequestrent l'ARN poly(A) et entrainent la mort cellulaire. Methodes: Une librairie d'ADNc provenant de cerveau foetal humain a ete utilisee pour chercher la proteine liant PABPNI au moyen du systeme a double-hybrides dans la levure. L'interaction proteine-proteine a ete confirmee par GST pull-down et co-immunoprecipitation. Le modele cellulaire de DMOP et le tissu musculaire provenant de patients atteints DMOP ont ete utilises pour verifier si les proteines liant PABPNI etaient impliquees dans la formation des inclusions intranucleaires dans la DMOP. Resultats: Nous avons identifie deux proteines interagissant avec PABPN1, hnRNP A1 et hnRNP A/B. En co-expression avec PABPN1m dans des cellules COS-7, les proteines hnRNP A1 et A/B a predominance nucleaire se retrouvent avec PABPN1m dans les agregats intranucleaires insolubles. Des etudes chez les patients atteints de DMOP ont montre que hnRNP A I est sequestre dans les inclusions nucleaires. Conclusions: Les proteines hnRNP sont impliquees dans la maturation de l'ARNm et le transport nucleocytoplasmique de l'ARNm. La sequestration de hnRNPs dans les agregats intranucleaires appuie l'hypothese selon laquelle les inclusions intranucleaires de la DMOP sont des pietes a ARN poly(A) qui interferent avec le transport de l'ARN et causent la mort des cellules musculaires.

Mutation screening of the ALS2 gene in sporadic and familial amyotrophic lateral sclerosis.

Abstract: Background Mutations in the ALS2 gene cause juvenile-onset autosomal recessive amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia. Objective To assess the role of ALS2 among more common forms of ALS. Methods DNA from 95 unrelated familial, 95 unrelated sporadic, and 11 early-onset ALS patients was screened for mutations in ALS2 by denaturing high-performance liquid chromatography and direct sequencing of polymerase chain reaction–amplified fragments. Each variant identified was also analyzed among control subjects. All 34 exons of ALS2 plus the 5′ and 3′ untranslated region were screened. Results We detected 23 novel sequence variants; however, none is disease-associated. Conclusion Mutations of ALS2 are not a common cause of ALS.

Progress in understanding the pathogenesis of oculopharyngeal muscular dystrophy.

Abstract: Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping (ptosis), swallowing difficulties (dysphagia), and proximal limb weakness. The autosomal dominant form of this disease is caused by expansions of a (GCG)6 repeat to (GCG)8-13 in the PABPN1 gene. These mutations lead to the expansion of a polyalanine stretch from 10 to 12-17 alanines in the N-terminal domain of PABPN1. Mutated PABPN1 (mPABPN1) induces the formation of muscle intranuclear inclusions that are thought to be the hallmark of this disease. In this review, we discuss: 1) OPMD genetics and PABPN I function studies; 2) diseases caused by polyalanine expansions and cellular polyalanine toxicity; 3) mPABPN1-induced intranuclear inclusion toxicity; 4) role of oligomerization of mPABPNI in the formation and toxicity of OPMD intranuclear inclusions and; 5) recruitment of subcellular components to the OPMD inclusions. We present a potential molecular mechanism for OPMD pathogenesis that accounts for these observations.

Linkage to the CCM2 locus and genetic heterogeneity in familial cerebral cavernous malformation.

Abstract: Contexte: La malformation caverneuse cerebrale (CCM) est une forme de maladie vasculaire intracrânienne qui survient de facon sporadique mais qui peut aussi avoir un mode d'heredite dominant. Des analyses de liaison ont montre une heterogeneite genetique parmi les formes dont l'heredite est dominante, suggerant l'existence d'au moins trois locus, CCM1, CCM2 et CCM3. Methodes: Dans cette etude, nous avons evalue cinq familles presentant une CCM a heredite dominante pour determiner la presence de mutations dans le gene CCM I au moyen de la chromatographie en phase liquide a haute performance denaturante. Nous avons ensuite procede a une analyse de liaison et a un haplotypage dans ces cinq familles au moyen de marqueurs tres polymorphes des genes candidats CCM. Resultats: Aucune mutation dans le gene CCM1 n'a ete demontree dans les cinq familles etudiees au moyen de marqueurs tres polymorphes. Nous avons identifie par haplotypage trois familles ou il y a segregation d'alleles de CCM2 avec la maladie et deux familles ou il y a segregation d'alleles de CCM3 avec la maladie. Nous avons confirme au moyen de l'analyse de liaison, qu'une famille avait un Lod score positif de 2,03 (p<0,0001) au locus CCM2 en utilisant le marqueur D7S678. Conclusions: Cette etude est la premiere a reproduire une liaison au locus CCM2 et identifie une cinquieme famille dans laquelle la maladie est liee a ce gene. Elle supporte egalement le concept d'une heterogeneite genetique dans la CCM en identifiant quatre autres familles ou on n'a pas decele de mutation dans le gene CCM1.

NF2 tumor suppressor gene: a comprehensive and efficient detection of somatic mutations by denaturing HPLC and microarray-CGH.

Abstract: The NF2 tumor suppressor gene, located in chromosome 22q12, is involved in the development of multiple tumors of the nervous system, either associated with neurofibromatosis 2 or sporadic ones, mainly schwannomas and meningiomas. In order to evaluate the role of the NF2 gene in sporadic central nervous system (CNS) tumors, we analyzed NF2 mutations in 26 specimens: 14 meningiomas, 4 schwannomas, 4 metastases, and 4 other histopathological types of neoplasms. Denaturing high performance liquid chromatography (denaturing HPLC) and comparative genomic hybridization on a DNA microarray (microarray- CGH) were used as scanning methods for small mutations and gross rearrangements respectively. Small mutations were identified in six out of seventeen meningiomas and schwannomas, one mutation was novel. Large deletions were detected in six meningiomas. All mutations were predicted to result in truncated protein or in the absence of a large protein domain. No NF2 mutations were found in other histopathological types of CNS tumors. These results provide additional evidence that mutations in the NF2 gene play an important role in the development of sporadic meningiomas and schwannomas. Denaturing HPLC analysis of small mutations and microarray-CGH of large deletions are complementary, fast, and efficient methods for the detection of mutations in tumor tissues.

A Comprehensive and Efficient Detection of Somatic Mutations by Denaturing HPLC and Microarray-CGH

Abstract: The NF2 tumor suppressor gene, located in chromosome 22q12, is involved in the development of multiple tumors of the nervous system, either associated with neurofibromatosis 2 or sporadic ones, mainly schwannomas and meningiomas. In order to evaluate the role of the NF2 gene in sporadic central nervous system (CNS) tumors, we analyzed NF2 mutations in 26 specimens: 14 meningiomas, 4 schwannomas, 4 metastases, and 4 other histopathological types of neoplasms. Denaturing high performance liquid chromatography (denaturing HPLC) and comparative genomic hybridization on a DNA microarray (microarray- CGH) were used as scanning methods for small mutations and gross rearrangements respectively. Small mutations were identified in six out of seventeen meningiomas and schwannomas, one mutation was novel. Large deletions were detected in six meningiomas. All mutations were predicted to result in truncated protein or in the absence of a large protein domain. No NF2 mutations were found in other histopathological types of CNS tumors. These results provide additional evidence that mutations in the NF2 gene play an important role in the development of sporadic meningiomas and schwannomas. Denaturing HPLC analysis of small mutations and microarray-CGH of large deletions are complementary, fast, and efficient methods for the detection of mutations in tumor tissues.

Severe neuropathy with agenesis of the corpus callosum

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