Showing papers by "Guy A. Rouleau published in 2004"

Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates.

Abstract: Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons. We identified two large pedigrees segregating the disorder in an isolated population living in Newfoundland and performed a 5-cM genome scan. Linkage analysis identified a locus mapping to 12p13.33 with a maximum LOD score of 8.4. Haplotype sharing defined a candidate interval of 1.06 Mb containing all or part of seven annotated genes, sequencing of which failed to detect causative mutations. Comparative genomics revealed a conserved ORF corresponding to a novel gene in which we found three different truncating mutations among five families including patients from rural Quebec and Nova Scotia. This gene, termed “HSN2,” consists of a single exon located within intron 8 of the PRKWNK1 gene and is transcribed from the same strand. The HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells.

The 14q restless legs syndrome locus in the French Canadian population.

Abstract: A new restless legs syndrome locus on chromosome 14 recently has been reported in one family of Italian origin. Our study aimed to replicate this finding and determine the importance of this locus in the French Canadian population. Markers spanning the region were genotyped in 14 large families and linkage assessed using two-point and multipoint logarithm of odds scores. Possible linkage to this locus was found in one of our kindreds providing support for the existence of this locus and indicating that this locus may be responsible for a small fraction of French Canadian restless legs syndrome.

Tourette syndrome and dopaminergic genes: a family-based association study in the French Canadian founder population.

Abstract: Tourette syndrome and dopaminergic genes: a family-based association study in the French Canadian founder population

Restless legs in Tourette syndrome.

Abstract: Restless legs syndrome (RLS) and Tourette's syndrome (TS) share some common features, including the phenomenology of sensations relieved by movements, but few studies have examined the links between RLS and TS. We examined RLS and other TS comorbidities in 144 probands with TS or chronic tics and their parents. RLS was present in 10% of probands and 23% of parents with no gender differences. RLS in probands was linked significantly to maternal RLS but not paternal RLS, suggesting that a maternal RLS factor may contribute to the variable expression of TS.

A novel locus for pure recessive hereditary spastic paraplegia maps to 10q22.1-10q24.1.

Abstract: The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by progressive lower-limb spasticity. In this study, we performed linkage analysis on an autosomal recessive pure HSP family and mapped the disease to chromosome 10q22.1-10q24.1, a locus partially overlapping the existing SPG9 locus. We have either identified a novel locus for pure recessive HSP (SPG27), or we have found the first case of allelic disorders with different mode of inheritance in HSP. If the disorders are indeed allelic, our results have reduced the SPG9 interval by 3Mb with D10S536 and D10S1758 as flanking markers.

A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family.

Abstract: Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder clinically characterized by distal and proximal sensory loss that is caused by the reduction or absence of peripheral sensory nerves. Recently, a novel gene called HSN2 has been found to be the cause of HSAN type II in five families from Newfoundland and Quebec. Screening of this gene in an HSAN type II Lebanese family showed a 1bp deletion mutation found in a homozygous state in all affected individuals. This novel mutation supports the hypothesis that HSN2 is the causative gene for HSAN type II.

Mutational analysis of neurotensin in familial restless legs syndrome

Abstract: A susceptibility locus for restless legs syndrome (RLS) has been identified recently on chromosome 12q. This region contains several transcribed genes including neurotensin (NTS), which, as an important modulator of the dopaminergic transmission, represents a strong functional and positional candidate in the context of RLS. In this study, NTS was evaluated for mutational analysis. A panel of 19 individuals from 4 families supporting linkage to 12q was investigated using a combined denaturing high-performance liquid chromatography (dHPLC) and direct sequencing method. Analysis of the NTS genomic sequence revealed 2 intronic polymorphisms and 1 variant located in the 5' untranslated region (UTR). None of the observed variants co-segregated with RLS and no disease-associated polymorphisms were detected in any of the analyzed families. Based on these results, it is unlikely that NTS is the gene responsible for RLS in chromosome 12-linked families.

Association between 7q31 markers and Tourette syndrome.

Abstract: Tourette syndrome (TS) is a complex neuropychiatric disorder with a strong genetic basis. Although no specific susceptibility genes have been identified for TS, cytogenetic studies in selected cases suggest the existence of a predisposing gene located in the 7q31 chromosomal region. In order to test the hypothesis of a possible relationship between this region and TS at the population level, we undertook a family based association study in a sample of French Canadian patients from Quebec. For this purpose, markers D7S522, D7S523, and D7S1516 were tested using the extended transmission disequilibrium test (e-TDT). Marker D7S522 showed a biased transmission of alleles from heterozygote parents to their TS offsprings (allele-wise TDT chi(2) = 12.61, 4 df, P = 0.013, genotype-wise TDT chi(2) = 15.49, 7 df, P = 0.030). When the analysis was restricted to patients without ADHD or OCD comorbidity, similar results were observed both allele and genotype-wise (chi(2) = 10.68, 4 df, P = 0.03 and chi(2) = 12.55, 5 df, P = 0.028, respectively). In addition, marker D7S523 was also associated (allele-wise TDT chi(2) = 18.37, 7 df, P = 0.01 and genotype-wise TDT chi(2) = 46.26, 17 df, P = 0.00016), and showed a tendency for association in the comorbidity-free subgroup (genotype-wise TDT chi(2) = 18.7, 10 df, P = 0.044). Finally, marker D7S1516, contained in the inner mitochondrial membrane peptidase 2 like (IMMP2L) gene, also showed a tendency for association (genotype-wise TDT chi(2) = 32.87, 21 df, P = 0.048). These results may reflect the proximity of markers D7S522, D7S523, and possibly D7S1516 to a gene or regulatory region relevant to TS predisposition.

A founder effect in three large Newfoundland families with a novel clinically variable spastic ataxia and supranuclear gaze palsy.

Abstract: A distinctive slowly progressive neurodegenerative disorder, which falls under a new category of neurological diseases, the hereditary spastic ataxias (HSA), is described in three independently ascertained Newfoundland kindreds. HSA is a heterogeneous group of disorders in which pyramidal tract features overlap cerebellar characteristics. The families are assumed to have the same condition as, although apparently unrelated, all originate in a historically isolated cluster of rural communities and link to the same locus at 12p13, SAX1. Clinically the phenotype is very variable but lower limb hypertonicity and hyperreflexia are early and prominent generally preceded by eye movement abnormality, an impaired vertical downward saccade and a typical involuntary head jerk. These are followed by variable levels of ataxia, dysarthria, and dysphagia. Onset occurs in the first two decades and can be detected in most by early adulthood. Significant mobility problems are present by the fourth decade with a broad based ataxic and spastic gait. MRI scans of brain and spinal cord were normal. Neuropathology showed degeneration of corticospinal tracts and posterior columns and midbrain neuronal loss. The phenotype is striking in its diversity among and within families and the variability of expression can be observed within the same sibship. Pedigree analysis shows no evidence of anticipation or any sex differences in severity. The condition is unusually prevalent in the province of Newfoundland, which is characteristic of a founder effect followed by isolation and large family size. Fine mapping efforts have reduced the critical interval of the SAX1 locus to 1.9Mb. Identification of the SAX1 gene will help to clarify the pathogenesis of this type of HSA.

TAU mutations are not a predominant cause of frontotemporal dementia in Canadian patients.

Abstract: Objectif: La demence fronto-temporale est une maladie neurodegenerative touchant surtout les lobes frontaux et/ou temporaux, avec perte neuronale et intraneuronale et/ou inclusions intragliales composees de la forme hyperphosphorylee de la proteine tau et d'ubiquitine associees aux microtubules. Des mutations dans le gene TAU ont ete identifiees chez a peu pres 15 % de tous les cas de demence fronto-temporale. Nous avons evalue l'implication des mutations du gene TAU dans le developpement de la demence fronto-temporale chez des patients d'origine canadienne francaise et anglaise. Methodes: Quatorze patients atteints de demence fronto-temporale et 95 temoins normaux ont ete recrutes pour participer a l'etude. Le gene TAU a ete sequence et soumis a la chromatographie haute performance en phase liquide denaturante pour detecter la presence de mutations. Resultats: Aucune mutation, sauf de nouveaux polymorphismes, n'a ete detectee dans le gene TAU de ces patients. Cependant, un polymorphisme pourrait jouer un role dans la pathogenese. Conclusion: Nos resultats sont conformes aux travaux anterieurs suggerant que les mutations dans ce gene ne sont par une cause frequente de demence fronto-temporale chez les patients canadiens.