Showing papers by "Guy A. Rouleau published in 1994"
TL;DR: It is proposed that changes in the KSP-repeat domain may affect the cross-linking properties of the heavy neurofilaments subunit and perhaps contribute to the development of neurofilamentous swellings in motor neurons, a hallmark of ALS.
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting motor neurons. The etiology of the majority of cases remains unknown. Recent findings from several laboratories suggest a role for neurofilaments in the development of motor neuron disorders. The C-terminal region of the human neurofilament heavy subunit (NEFH) contains a unique functional domain consisting of 43 repeat motifs of the amino acids Lys-Ser-Pro (KSP). This C-terminal region of NEFH forms the sidearm projections which cross-link the neurofilaments. Previously, we have demonstrated polymorphism in the C-terminal region of the human NEFH: an allelic variant of a slightly larger molecular size, containing an additional KSP phosphorylation motif. Novel mutations in this region were found in five ALS patients. We propose that changes in the KSP-repeat domain may affect the cross-linking properties of the heavy neurofilament subunit and perhaps contribute to the development of neurofilamentous swellings in motor neurons, a hallmark of ALS.
465 citations
TL;DR: The hypothesis that loss of function of schwannomin is a frequent and fundamental event in the genesis ofSchwannomas is supported, based on the identification of inactivate mutation in NF2 patients.
Abstract: Schwannomas are tumors arising from schwann cells surrounding peripheral nerves. Although most schwannomas are sporadic, they are seen in approximately 90% of individuals with neurofibromatosis type 2 (NF2), an autosomal dominantly inherited disease with an incidence of 1:40000 live births. The NF2 gene has recently been isolated on chromosome 22 and encodes a putative membrane organizing protein named schwannomin. It is believed to act as a tumor suppressor gene based on the high frequency of loss of heterozygosity (LOH) on this autosome in both sporadic and NF2 associated schwannomas and meningiomas and the identification of inactivating mutation in NF2 patients. In this study we examined 61 schwannomas including 48 sporadic schwannomas (46 of which are vestibular schwannomas) and 12 schwannomas obtained from NF2 patients, for mutations in 10 of the 16 coding exons of the NF2 gene. Twelve inactivating mutations were identified, 8 in sporadic tumours and 4 in tumors from people with NF2. These results support the hypothesis that loss of function of schwannomin is a frequent and fundamental event in the genesis of schwannomas.
136 citations
TL;DR: No mutations were found in Chamorros with ALS or PD, indicating that mutations in the SOD-1 gene do not underlie the high-incidence neurodegenerative disorders of Guam.
Abstract: GUAM is one of three endemic foci whose indigenous (Chamorro) people have an unusually high incidence of fatal neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and Parkinsonism—dementia (PD). Recently, mutations in the Cu/Zn superoxide dismutase (SOD-1) gene have been identified in s
36 citations
TL;DR: The results suggest that increased ros expression may play a role in tumorigenesis in a significant proportion of gliomas, suggesting a possible role for these oncogenes in individual tumors but no generalized role in development or progression of human glioma.
25 citations
TL;DR: The NF2 gene is the first example of a tumor suppressor gene whose protein product appears to act as a membrane cytoskeleton-linker and it is suggested that the analysis of the mouseNF2 gene might yield insights into the function of the human gene.
Abstract: Neurofibromatosis type 2 (NF2) is a complex nervous system disorder characterized by the development of schwannomas (especially vestibular), meningiomas, ependymomas and juvenile lens opacities. Mutation in the NF2 gene, which encodes for the schwannomin protein (SCH), a member of the band 4.1 superfamily of genes, predisposes carriers to these central nervous system tumors. We have isolated a mouse cDNA from a brain library which contains the complete open reading frame of the mouse homologue of the NF2 gene. This cDNA encodes for a 596 amino acid protein with 98% identity to the human SCH. Cross species hybridization experiments predict that the NF2 gene is highly conserved in other vertebrates. Northern analysis detects a 4.5 kb transcript in mouse brain, kidney, cardiac muscle, skin and lung suggesting ubiquitous expression. The predicted secondary structure of SCH, which is shared by all members of the band 4.1 superfamily, includes a highly conserved amino-terminal domain which is believed to bind to proteins in the plasma membrane and a large highly charged alpha-helix domain proposed to associate with the cytoskeleton. The NF2 gene is the first example of a tumor suppressor gene whose protein product appears to act as a membrane cytoskeleton-linker. These results show that the NF2 gene is highly conserved and suggests that the analysis of the mouse NF2 gene might yield insights into the function of the human gene.
24 citations
TL;DR: Linkage analysis using anonymous DNA markers that flank the three previously described loci significantly exclude the French-Canadian kindred from the SCA1, SCA2, and MJD loci, suggesting a fourth, still unmapped SCA locus remains to be identified.
15 citations
Journal Article•
TL;DR: The authors have studied a series of 23 DiGeorge syndrome patients by prometaphase chromosome analysis and/or by FISH with a set of 6 cosmid probes spanning the previously described commonly deleted region, finding that only the most telomeric of these loci is conserved.
Abstract: Les auteurs ont etudie 23 patients atteints de syndrome de DiGeorge par analyse chromosomique prometaphasique et par la technique d'hybridation in situ fluorescente. Six sondes cosmidiques couvrant la region communement deletee ont ete utilisees. Quatre patients ont une deletion de la bande 22q11.2 visible cytogenetiquement, tandis que les 18 autres patients presentent une deletion moleculaire, detectable uniquement par hybridation in situ. Pour 21 patients, la deletion comprend les 6 loci analyses, alors que pour un autre, le locus le plus telomerique demeure conserve. Le dernier patient n'est delete pour aucune des sondes utilisees
13 citations
TL;DR: Analysis of the allele distribution in AKXD recombinant inbred strains using a simple sequence repeat polymorphism in the 3' untranslated region of the mouse cDNA maps the mouse NF2 gene to the proximal region of chromosome 11, closely linked to Pmv-2.
8 citations
TL;DR: The development of a number of highly informative simple sequence repeat polymorphisms in the region of linkage-21q21 through 21q22-has permitted us to confirm both the assignment of ALS1 to 21q and the genetic heterogeneity of FALS, and to refine the mapping ofALS1, based on recombination events in two of the linked families.
8 citations
TL;DR: The authors suggest that in newborns with unexplained apnea, MRI of the craniocervical junction is indicated and certain patients may be discovered who have less compromised cervicomedullary function and are afflicted by less aggressive forms of neurofibromatosis type 1.
Abstract: The authors report, for the first time, the finding by magnetic resonance imaging of a neurofibroma at the craniocervical junction with upper cervical cord and lower brainstem compression causing complete apnea from birth. Subsequent subtotal resection of the neurofibroma resulted in the successful extubation of a previously ventilator-dependent patient. After a two month period of breathing spontaneously, the newborn developed an upper respiratory tract infection and was reintubated. The patient, unable to be weaned off of the respirator, was extubated and expired shortly thereafter, at the age of five months. The authors suggest that in newborns with unexplained apnea, MRI of the cranio-cervical junction is indicated. Certain patients may be discovered who have less compromised cervico-medullary function and are afflicted by less aggressive forms of neurofibromatosis type 1. These patients may benefit permanently from a surgical decompression.
6 citations
TL;DR: The abstracts have been reviewed and edited by T.V. Harding, J. Paulson, G. Said, and K. Thomas.
TL;DR: The results obtained allowed us to assess the importance of knowing the carrier and removal status of canine coronavirus, as a source of infection for other animals, not necessarily belonging to the same breeds.
Abstract: A. N. Mhatre, M. A. Trifiro, M. Kaufman, P. Kazemi-Esfarjani, D. Figlewicz, G. Rouleau & L. Pinsky Nature Genetics 5,184–188 (1993) The acknowledgements that appeared in this paper were incorrect. The acknowledgements that were part of this paper are printed below. Acknowledgements We are grateful to D.
TL;DR: It is demonstrated that MJD and SCA2 are genetically distinct despite similarities in disease phenotype and ancestral origins of the patients, providing further evidence for genetic heterogeneity within these disorders.
Abstract: Machado Joseph disease (MJD) is a progressive, spinocerebellar ataxia (SCA) with an autosomal dominant mode of inheritance and almost complete penetrance. Clinically, it is difficult to distinguish it from other autosomal dominantly inherited ataxias, and it has been suggested that MJD may be caused by an allelic variant of SCA. Exclusion of MJD from the SCA1 locus on chromosome 6p has previously been demonstrated. However, following the recent assignment of a second locus for spinocerebellar ataxia (SCA2) to chromosome 12q in a large Cuban kindred of Spanish origin, we have investigated linkage in MJD families using the two markers, D12S58 and PLA2, that flank this disease gene. The MJD locus was definitively excluded from an interval spanning approximately 70 cM, which includes these loci. These studies demonstrate that MJD and SCA2 are genetically distinct despite similarities in disease phenotype and ancestral origins of the patients. Thus, the as yet unmapped MJD locus represents a third SCA locus, providing further evidence for genetic heterogeneity within these disorders.
Journal Article•
TL;DR: This work has studied one large French Canadian kindred with four generations of living affected individuals segregating an autosomal dominant form of SCA, and linkage analysis using anonymous DNA markers which flank the four previously described loci significantly excludes the FrenchCanadian kindred from the SCA-1,SCA-2, SCa-3/MJD and SCA -4 loci.
Abstract: The autosomal dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders. To date, four loci have been identified: the SCA-1 locus (on chromosome (chr) 6p), the SCA-2 locus (on chr 12q), the SCA-3/MJD locus (on chr 14q), and more recently an SCA-4 locus was described (chr 16q) in a Utah kindred. We have studied one large French Canadian kindred with four generations of living affected individuals segregating an autosomal dominant form of SCA. Linkage analysis using anonymous DNA markers which flank the four previously described loci significantly excludes the French Canadian kindred from the SCA-1, SCA-2, SCA-3/MJD and SCA-4 loci. Therefore a fifth, still unmapped, SCA locus remains to be identified.