Showing papers by "Guy A. Rouleau published in 1998"

Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy

Abstract: Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution. It usually presents in the sixth decade with progressive swallowing difficulties (dysphagia), eyelid drooping (ptosis) and proximal limb weakness. Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark. We isolated the poly(A) binding protein 2 gene (PABP2) from a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manuscript submitted). A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD. Thus the (GCG)7 allele is an example of a polymorphism which can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.

Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.

Abstract: Lafora's disease (LD; OMIM 254780) is an autosomal recessive form of progressive myoclonus epilepsy characterized by seizures and cumulative neurological deterioration. Onset occurs during late childhood and usually results in death within ten years of the first symptoms. With few exceptions, patients follow a homogeneous clinical course despite the existence of genetic heterogeneity. Biopsy of various tissues, including brain, revealed characteristic polyglucosan inclusions called Lafora bodies, which suggested LD might be a generalized storage disease. Using a positional cloning approach, we have identified at chromosome 6q24 a novel gene, EPM2A, that encodes a protein with consensus amino acid sequence indicative of a protein tyrosine phosphatase (PTP). mRNA transcripts representing alternatively spliced forms of EPM2A were found in every tissue examined, including brain. Six distinct DNA sequence variations in EPM2A in nine families, and one homozygous microdeletion in another family, have been found to cosegregate with LD. These mutations are predicted to cause deleterious effects in the putative protein product, named laforin, resulting in LD.

Vocal Cord and Pharyngeal Weakness with Autosomal Dominant Distal Myopathy: Clinical Description and Gene Localization to 5q31

Abstract: Distal myopathy refers to a heterogeneous group of disorders in which the initial manifestations are weakness and atrophy of the hands and feet. We report a family segregating an autosomal dominant distal myopathy, with multiple affected individuals in whom vocal cord and pharyngeal weakness may accompany the distal myopathy, without involvement of the ocular muscles. To our knowledge, this pedigree displays a distinct distal myopathy with the added features of pharyngeal and vocal cord dysfunction (VCPDM) that has not been previously reported. We mapped the MPD2 gene for VCPDM to chromosome 5q within a 12-cM linkage interval between markers D5S458 and D5S1972 in a large pedigree (a maximum LOD score of 12.94 at a recombination fraction of 0 for D5S393) and combined genome screening and DNA pooling successfully adapted to fluorescent markers. This technique provides for the possibility of fully automated genome scans.

Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder.

Abstract: Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stablize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a γ-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 ± 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients (χ2 = 8.09; empirical P = 0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19–3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD = 1.45; empirical P = 0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is implicated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined.

Identification of six novel SOD1 gene mutations in familial amyotrophic lateral sclerosis.

Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature death of motor neurons. In approximately 10% of the cases the disease is inherited as autosomal dominant trait (FALS). It has been found that mutations in the Cu/Zn superoxide dismutase gene (SOD1) are responsible for approximately 15% of FALS kindreds. We screened affected individuals from 70 unrelated FALS kindreds and identified 10 mutations, 6 of which are novel. Surprisingly, we have found a mutation in exon 3, which includes most of the active site loop and Zn2+ binding sites, a region where no previous SOD1 mutations have been found. Our data increase the number of different SOD1 mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protein.

Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families.

Abstract: The spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. To date, eight different loci causing SCA have been identified: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, SCA6, SCA7, and dentatorubropallidoluysian atrophy (DRPLA). Expansion of a CAG repeat in the disease genes has been found in five of these disorders. To estimate the relative frequencies of the SCA1, DRPLA, MJD, SCA2, and SCA6 mutations among Portuguese ataxia patients, we collected DNA samples from 48 ataxia families and performed polymerase chain reaction (PCR) amplification of the CAG repeat mutations on chromosomes 6p, 12p, 14q, 12q, and 19p, respectively. Fifty-five individuals belonging to 34 dominant families (74%) had an expanded CAG repeat at the MJD gene. In five individuals from two kindreds with a dominant pattern of inheritance (4%), an expanded CAG repeat at the SCA2 gene was found. In MJD patients, the normal allele size ranged from 13 to 41, whereas the mutant alleles contained 65 to 80 repeats. For the SCA2 patients, normal alleles had 22 or 23, while expanded alleles had between 36 and 47 CAG units. We did not find the SCA1, DRPLA, or SCA6 mutations in our group of families. The MJD mutation remains the most common cause of SCA in Portugal, while a small number of cases are caused by mutations at the SCA2 gene, and 22% are due to still unidentified genes.

Brain Glyceraldehyde-3-Phosphate Dehydrogenase Activity in Human Trinucleotide Repeat Disorders

Abstract: Background Although the abnormal gene products responsible for several hereditary neurodegenerative disorders caused by repeat CAG trinucleotides have been identified, the mechanism by which the proteins containing the expanded polyglutamine domains cause cell death is unknown The observation that several of the mutant proteins interact in vitro with the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) suggests that interaction between the different gene products and GAPDH might damage brain neurons Objective To measure the activity of GAPDH in postmortem brain of patients with CAG repeat disorders Patients and Methods Activity of GAPDH was measured in morphologically affected and unaffected brain areas of patients with 4 different CAG repeat disorders (Huntington disease, spinocerebellar ataxia 1 [SCA1], SCA2, and SCA3–Machado-Joseph disease), in brains of patients with Friedreich ataxia (a GAA repeat disorder) and Alzheimer disease, and in brains of matched control subjects Results Brain GAPDH activity was normal in all groups with the exception of a slight but statistically significant region-specific reduction in the patients with Huntington disease (caudate nucleus, −12%) and Alzheimer disease (temporal cortex, −19%) Conclusion The presence of the polyglutamine-containing proteins in CAG repeat disorders does not result in substantial irreversible inactivation or in increased activity of GAPDH in human brain

Prenatal diagnosis of Machado–Joseph disease by direct mutation analysis

Abstract: MJD is the most frequent dominant ataxia and an incapacitating disorder. Onset is most frequently during the reproductive years, and genetic counselling is its only means of prevention. The causative mutation—an expansion of a (CAG)n on chromosome 14q32.1—can now be directly detected. We now report the first two cases of prenatal diagnosis (PND). The first presented as a simultaneous request for predictive testing and PND at 14 weeks of pregnancy. Owing to time constraints, we performed a full protocol of counselling with shorter intervals between sessions, while psycho-social evaluation of the other parent and obstetric consults were also begun. We ensured that the couple wished termination if the fetus was a carrier, to avoid a presymptomatic test for the unborn child. We were thus able to deliver test results two weeks before PND. As the fetus carried an expanded allele (77 CAGs) inherited from his father, termination was performed and the couple received counselling, psychological and social support. The second case was the fetus of a carrier-mother that was diagnosed as non-carrier, also after amniocentesis. © 1998 John Wiley & Sons, Ltd.

Anticipation in familial cavernous angioma: ascertainment bias or genetic cause

Abstract: OBJECTIVES: Anticipation has been linked to unstable trinucleotide repeats in many neurological disorders. We examined the hypothesis of genetic anticipation in familial cavernous angioma (FCA) of the central nervous system. MATERIAL AND METHODS: The mean ASO of affected individuals was compared between successive generations in 55 families. Intergenerational pair-wise comparisons were employed to avoid several ascertainment biases. Regarding severity of disease both type of manifestation and number of cavernous angiomas were compared between generations. RESULTS: The mean ASO decreased significantly both from the first to the second generation (31.6 vs 17.8 years; P = 0.000) and from the second to the third generation (17.8 vs 6.7 years; P = 0.002). The pair-wise comparisons also showed significantly earlier ASO. No clear evidence for anticipation with regard to severity of disease was found. CONCLUSIONS: Molecular genetic studies will determine whether trinucleotide repeats are the underlying mechanism for our observation of anticipation in FCA.

ALLELIC VARIANTS OF THE PHOSPHOLIPASE C-η1 GENE ASSOCIATED WITH BIPOLAR DISORDER

Abstract: The present invention relates to the use of phospholipase C-η1 gene for the diagnosis, prognosis and development of treatments of bipolar disorder and/or lithium response. There is provided a method for the identification of patient with susceptibility to bipolar disorder and/or lithium response, which comprises the steps of: a) obtaining a nucleic acid sample of the patient; and b) determining allelic variants of phospholipase C-η1 gene present in the sample, and wherein certain allelic variants are indicative of a risk of pipolar disorder and/or lithium response.

Short GCG expansions in the PAB II gene for oculopharyngeal muscular dystrophy and diagnostic thereof

Abstract: The present invention relates to a human PAB II gene containing transcribed polymorphic GCG repeat, which comprises a sequence as set forth in SEQ ID NO:3, which includes introns and flanking genomic sequence. The allelic variants of GCG repeat of the human PAB II gene are associated with a disease related with protein accumulation in nucleus, such as polyalanine accumulation, a disease related with swallowing difficulties, such as oculopharyngeal muscular dystrophy. The present invention also relates to a method for the diagnosis of a disease with protein accumulation in nucleus, which comprises the steps of: a) obtaining a nucleic acid sample of said patient; and b) determining allelic variants of GCG repeat of the gene of claim 1, and wherein long allelic variants are indicative of a disease related with protein accumulation in nucleus.

Polymorphic cag repeat-containing gene and uses thereof

Abstract: The present invention relates to hGT1 gene, a polymorphic CAG repeat-containing gene and its uses thereof for the diagnosis, prognosis and treatment of psychiatric diseases, such as schizophrenia.

ALLELES DU GENE PHOSPHOLIPASE C-η1 ASSOCIE AU TROUBLE BIPOLAIRE

Abstract: La presente invention porte sur l'utilisation du gene phospholipase C-η1 associe au diagnostic, au pronostic et au developpement de traitements des troubles bipolaires et/ou de la reaction au lithium. L'invention porte egalement sur un procede d'identification du patient susceptible d'etre affecte par un trouble bipolaire et/ou reagissant au lithium, ce procede consistant a: a) prelever sur le patient un echantillon d'acide nucleique; et b) determiner les alleles du gene phospholipase C-η1 present dans l'echantillon, certains alleles presentant un risque de trouble bipolaire et/ou de reaction au lithium.