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Judith Melki - One of the best experts on this subject based on the ideXlab platform.
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correlation between severity and smn protein level in spinal muscular atrophy
Nature Genetics, 1997Co-Authors: Suzie Lefebvre, Peter Burlet, Solange Bertrandy, Olivier Clermont, Arnold Munnich, Gideon Dreyfuss, Judith MelkiAbstract:Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord. Three different forms of childhood SMA have been recognized on the basts of age at onset and clinical course: Werdnig-Hoffmann Disease (type l), the intermediate form (type II) and Kugelberg-Welander Disease (type III)1. A gene termed ‘survival of motor neuron’ (SMN) has been recognized as the Disease-causing gene in SMA2–6. SMN encodes a protein located within a novel nuclear structure and interacts with RNA-binding proteins7. To elucidate the molecular mechanism underlying the pathogenesis of the Disease, we examined the expression of the SMN gene in both controls and SMA patients by western blot and immunohistochemical analyses using antibodies raised against the SMN protein. The present study shows a marked deficiency of the SMN protein in SMA.
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Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene
Annals of neurology, 1997Co-Authors: Ruth Navon, Judith Melki, Michel Fardeau, Rami Khosravi, Liat Drucker, Bertrand Fontaine, Jean Claude Turpin, Bathein N'guyen, Pierre Rondot, Nicole BaumannAbstract:Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander Disease) and in GM2 gangliosidosis, Diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.
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Large scale deletions of the 5q13 region are specific to Werdnig-Hoffmann Disease.
Journal of medical genetics, 1996Co-Authors: Peter Burlet, Suzie Lefebvre, Olivier Clermont, Arnold Munnich, Lydie Burglen, Louis Viollet, Judith MelkiAbstract:Spinal muscular atrophy (SMA) is characterised by degeneration of anterior horn cells of the spinal cord and represents the second most common, lethal, autosomal recessive disorder after cystic fibrosis. Based on the criteria of the Internatinal SMA Consortium, childhood SMAs are classified into type I (Werdnig-Hoffmann Disease), type II (intermediate form), and type III (Kugelberg-Welander Disease). Recently, two genes have been found to be associated with SMA. The survival motor neurone gene (SMN) is an SMA determining gene as it is absent in 98.6% of patients. A second gene, XS2G3, or the highly homologous neuronal apoptosis inhibitory protein gene (NAIP) have been found to be more frequently deleted in type I than in the milder forms (types II and III). We investigated the correlation between the clinical phenotype and the genotype at this loci. A total of 106 patients were classified into type I (44), type II (31), and type III (31) and analysed using SMN, markers C212 and C272, and NAIP mapping upstream and downstream from SMN respectively. The combined analysis of all markers showed a large proportion of type I patients (43%) carried deletions of both SMN and its flanking markers (C212/272) and NAIP exon 5), as compared with none of the patients with type II or III SMA. The presence of large scale deletions involving these loci is specific to Werdnig-Hoffman Disease (type I) and allows one to predict the severity of the Disease in our series.
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gene for chronic proximal spinal muscular atrophies maps to chromosome 5q
Nature, 1990Co-Authors: Judith Melki, Peter Sheth, M F Bachelot, J P Carriere, A Marcadet, Alun Barois, Peter Burlet, Sonia Abdelhak, Jean Aicardi, Michel FardeauAbstract:PROXIMAL spinal muscular atrophies represent the second most common fatal, autosomal recessive disorder after cystic fibrosis1. The childhood form is classically subdivided into three groups: acute Werdnig-Hoffmann (type I), intermediate Werdnig-Hoffmann Disease (type II) and Kugelberg-Welander Disease (type III). These different clinical forms have previously been attributed to either genetic heterogeneity or variable expression of different mutations at the same locus2. Research has been hindered because the underlying biochemical defect is unknown, and there are insufficient large pedigrees with the most common and severe form (type I) available for study. Therefore, we have undertaken a genetic linkage analysis of the chronic forms of the Disease (types II and III) as an initial step towards the ultimate goal of characterizing the gene(s) responsible for all three types. We report here the assignment of the locus for the chronic forms to the long arm of chromosome 5 (5q 12–ql4), with the anonymous DNA marker D5S39, in 24 multiplex families of distinct ethnic origin. Furthermore, no evidence for genetic heterogeneity was found for types II and III in our study, suggesting that these two forms are allelic disorders.
Dawn S Chandler - One of the best experts on this subject based on the ideXlab platform.
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a humanized smn gene containing the smn2 nucleotide alteration in exon 7 mimics smn2 splicing and the sma Disease phenotype
Human Molecular Genetics, 2010Co-Authors: Jordan T Gladman, Thomas W Bebee, Chris Edwards, Dawn S Chandler, Mark M Rich, Zarife Sahenk, Xueyong WangAbstract:Proximal spinal muscular atrophy (SMA) is a neurodegenerative Disease caused by low levels of the survival motor neuron (SMN) protein. In humans, SMN1 and SMN2 encode the SMN protein. In SMA patients, the SMN1 gene is lost and the remaining SMN2 gene only partially compensates. Mediated by a C>T nucleotide transition in SMN2, the inefficient recognition of exon 7 by the splicing machinery results in low levels of SMN. Because the SMN2 gene is capable of expressing SMN protein, correction of SMN2 splicing is an attractive therapeutic option. Although current mouse models of SMA characterized by Smn knock-out alleles in combination with SMN2 transgenes adequately model the Disease phenotype, their complex genetics and short lifespan have hindered the development and testing of therapies aimed at SMN2 splicing correction. Here we show that the mouse and human minigenes are regulated similarly by conserved elements within in exon 7 and its downstream intron. Importantly, the C>T mutation is sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C>T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibit exon 7 skipping and mild adult onset SMA characterized by muscle weakness, decreased activity and an alteration of the muscle fibers size. This Smn C>T mouse represents a new model for an adult onset form of SMA (type III/IV) also know as the Kugelberg–Welander Disease.
Peter Burlet - One of the best experts on this subject based on the ideXlab platform.
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correlation between severity and smn protein level in spinal muscular atrophy
Nature Genetics, 1997Co-Authors: Suzie Lefebvre, Peter Burlet, Solange Bertrandy, Olivier Clermont, Arnold Munnich, Gideon Dreyfuss, Judith MelkiAbstract:Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord. Three different forms of childhood SMA have been recognized on the basts of age at onset and clinical course: Werdnig-Hoffmann Disease (type l), the intermediate form (type II) and Kugelberg-Welander Disease (type III)1. A gene termed ‘survival of motor neuron’ (SMN) has been recognized as the Disease-causing gene in SMA2–6. SMN encodes a protein located within a novel nuclear structure and interacts with RNA-binding proteins7. To elucidate the molecular mechanism underlying the pathogenesis of the Disease, we examined the expression of the SMN gene in both controls and SMA patients by western blot and immunohistochemical analyses using antibodies raised against the SMN protein. The present study shows a marked deficiency of the SMN protein in SMA.
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Large scale deletions of the 5q13 region are specific to Werdnig-Hoffmann Disease.
Journal of medical genetics, 1996Co-Authors: Peter Burlet, Suzie Lefebvre, Olivier Clermont, Arnold Munnich, Lydie Burglen, Louis Viollet, Judith MelkiAbstract:Spinal muscular atrophy (SMA) is characterised by degeneration of anterior horn cells of the spinal cord and represents the second most common, lethal, autosomal recessive disorder after cystic fibrosis. Based on the criteria of the Internatinal SMA Consortium, childhood SMAs are classified into type I (Werdnig-Hoffmann Disease), type II (intermediate form), and type III (Kugelberg-Welander Disease). Recently, two genes have been found to be associated with SMA. The survival motor neurone gene (SMN) is an SMA determining gene as it is absent in 98.6% of patients. A second gene, XS2G3, or the highly homologous neuronal apoptosis inhibitory protein gene (NAIP) have been found to be more frequently deleted in type I than in the milder forms (types II and III). We investigated the correlation between the clinical phenotype and the genotype at this loci. A total of 106 patients were classified into type I (44), type II (31), and type III (31) and analysed using SMN, markers C212 and C272, and NAIP mapping upstream and downstream from SMN respectively. The combined analysis of all markers showed a large proportion of type I patients (43%) carried deletions of both SMN and its flanking markers (C212/272) and NAIP exon 5), as compared with none of the patients with type II or III SMA. The presence of large scale deletions involving these loci is specific to Werdnig-Hoffman Disease (type I) and allows one to predict the severity of the Disease in our series.
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gene for chronic proximal spinal muscular atrophies maps to chromosome 5q
Nature, 1990Co-Authors: Judith Melki, Peter Sheth, M F Bachelot, J P Carriere, A Marcadet, Alun Barois, Peter Burlet, Sonia Abdelhak, Jean Aicardi, Michel FardeauAbstract:PROXIMAL spinal muscular atrophies represent the second most common fatal, autosomal recessive disorder after cystic fibrosis1. The childhood form is classically subdivided into three groups: acute Werdnig-Hoffmann (type I), intermediate Werdnig-Hoffmann Disease (type II) and Kugelberg-Welander Disease (type III). These different clinical forms have previously been attributed to either genetic heterogeneity or variable expression of different mutations at the same locus2. Research has been hindered because the underlying biochemical defect is unknown, and there are insufficient large pedigrees with the most common and severe form (type I) available for study. Therefore, we have undertaken a genetic linkage analysis of the chronic forms of the Disease (types II and III) as an initial step towards the ultimate goal of characterizing the gene(s) responsible for all three types. We report here the assignment of the locus for the chronic forms to the long arm of chromosome 5 (5q 12–ql4), with the anonymous DNA marker D5S39, in 24 multiplex families of distinct ethnic origin. Furthermore, no evidence for genetic heterogeneity was found for types II and III in our study, suggesting that these two forms are allelic disorders.
Michel Fardeau - One of the best experts on this subject based on the ideXlab platform.
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Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene
Annals of neurology, 1997Co-Authors: Ruth Navon, Judith Melki, Michel Fardeau, Rami Khosravi, Liat Drucker, Bertrand Fontaine, Jean Claude Turpin, Bathein N'guyen, Pierre Rondot, Nicole BaumannAbstract:Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander Disease) and in GM2 gangliosidosis, Diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.
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gene for chronic proximal spinal muscular atrophies maps to chromosome 5q
Nature, 1990Co-Authors: Judith Melki, Peter Sheth, M F Bachelot, J P Carriere, A Marcadet, Alun Barois, Peter Burlet, Sonia Abdelhak, Jean Aicardi, Michel FardeauAbstract:PROXIMAL spinal muscular atrophies represent the second most common fatal, autosomal recessive disorder after cystic fibrosis1. The childhood form is classically subdivided into three groups: acute Werdnig-Hoffmann (type I), intermediate Werdnig-Hoffmann Disease (type II) and Kugelberg-Welander Disease (type III). These different clinical forms have previously been attributed to either genetic heterogeneity or variable expression of different mutations at the same locus2. Research has been hindered because the underlying biochemical defect is unknown, and there are insufficient large pedigrees with the most common and severe form (type I) available for study. Therefore, we have undertaken a genetic linkage analysis of the chronic forms of the Disease (types II and III) as an initial step towards the ultimate goal of characterizing the gene(s) responsible for all three types. We report here the assignment of the locus for the chronic forms to the long arm of chromosome 5 (5q 12–ql4), with the anonymous DNA marker D5S39, in 24 multiplex families of distinct ethnic origin. Furthermore, no evidence for genetic heterogeneity was found for types II and III in our study, suggesting that these two forms are allelic disorders.
Arnold Munnich - One of the best experts on this subject based on the ideXlab platform.
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Clinical and Genetic Study of Algerian Patients with Spinal Muscular Atrophy
Journal of neurodegenerative diseases, 2013Co-Authors: Yamina Sifi, Arnold Munnich, K. Sifi, Assia Boulefkhad, Nourredine Abadi, Z. Bouderda, R. Cheriet, M. Magen, Jean-paul Bonnefont, C. BenlatrecheAbstract:Spinal muscular atrophy (SMA) is the second most common lethal autosomal recessive disorder. It is divided into the acute Werdnig-Hoffmann Disease (type I), the intermediate form (type II), the Kugelberg-Welander Disease (type III), and the adult form (type IV). The gene involved in all four forms of SMA, the so-called survival motor neuron (SMN) gene, is duplicated, with a telomeric (tel SMN or SMN1) and a centromeric copy (cent SMN or SMN2). SMN1 is homozygously deleted in over 95% of SMA patients. Another candidate gene in SMA is the neuronal apoptosis inhibitory protein (NAIP) gene; it shows homozygous deletions in 45–67% of type I and 20–42% of type II/type III patients. Here we studied the SMN and NAIP genes in 92 Algerian SMA patients (20 type I, 16 type II, 53 type III, and 3 type IV) from 57 unrelated families, using a semiquantitative PCR approach. Homozygous deletions of SMN1 exons 7 and/or 8 were found in 75% of the families. Deletions of exon 4 and/or 5 of the NAIP gene were found in around 25%. Conversely, the quantitative analysis of SMN2 copies showed a significant correlation between SMN2 copy number and the type of SMA.
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Detection of heterozygous SMN1 deletions in SMA families using a simple fluorescent multiplex PCR method.
Journal of Medical Genetics, 2001Co-Authors: Pascale Saugier-veber, Suzie Lefebvre, Arnold Munnich, Nathalie Drouot, Françoise Charbonnier, Elodie Vial, Thierry FrebourgAbstract:Editor—With a prevalence of 1/6000 live births, spinal muscular atrophy (SMA) represents the second most common fatal autosomal recessive disorder after cystic fibrosis.1 2 SMA is characterised by the degeneration of anterior horn cells of the spinal cord, resulting in progressive, symmetrical limb and trunk paralysis associated with muscular atrophy. This condition is clinically heterogeneous and has been subdivided into three types according to age of onset and clinical course3: type I (Werdnig-Hoffmann Disease, MIM 253300), type II (intermediate form, MIM 253550), and type III SMA (Kugelberg-Welander Disease, MIM 253400). The SMA locus has been mapped to chromosome 5q11.2-q13.3 within a region characterised by the large inverted duplication of a 500 kb element.4-6 The survival motor neurone ( SMN ) gene, which lies within this element, is duplicated and both copies are expressed. The telomeric gene ( SMN1 ) has been shown to be deleted or mutated in all three types of SMA.4 SMN1 encodes almost the full length transcript whereas the centromeric copy ( SMN2 ) generates alternatively spliced variants lacking the C-terminal sequence.5 7 The SMN region contains low copy repeats triggering homologous recombination events. Indeed, approximately 95% of SMA patients lack both SMN1 genes owing to either deletion or gene conversion.4 In SMA patients who lack only one SMN1 gene, allelic intragenic mutations have been identified, confirming the involvement of SMN1 in the pathogenesis of SMA.5 8-10 The heterozygote frequency has been estimated to be 1/40. However, the duplication of the SMA locus makes the detection of SMA carriers in the general population difficult, and this has hampered genetic counselling in affected families. Initial attempts to estimate the SMN copy number were based on the measurement of the SMN1 / SMN2 ratios,11-13 but the broad variability of SMN2 copy number hinders reliable …
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correlation between severity and smn protein level in spinal muscular atrophy
Nature Genetics, 1997Co-Authors: Suzie Lefebvre, Peter Burlet, Solange Bertrandy, Olivier Clermont, Arnold Munnich, Gideon Dreyfuss, Judith MelkiAbstract:Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord. Three different forms of childhood SMA have been recognized on the basts of age at onset and clinical course: Werdnig-Hoffmann Disease (type l), the intermediate form (type II) and Kugelberg-Welander Disease (type III)1. A gene termed ‘survival of motor neuron’ (SMN) has been recognized as the Disease-causing gene in SMA2–6. SMN encodes a protein located within a novel nuclear structure and interacts with RNA-binding proteins7. To elucidate the molecular mechanism underlying the pathogenesis of the Disease, we examined the expression of the SMN gene in both controls and SMA patients by western blot and immunohistochemical analyses using antibodies raised against the SMN protein. The present study shows a marked deficiency of the SMN protein in SMA.
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Large scale deletions of the 5q13 region are specific to Werdnig-Hoffmann Disease.
Journal of medical genetics, 1996Co-Authors: Peter Burlet, Suzie Lefebvre, Olivier Clermont, Arnold Munnich, Lydie Burglen, Louis Viollet, Judith MelkiAbstract:Spinal muscular atrophy (SMA) is characterised by degeneration of anterior horn cells of the spinal cord and represents the second most common, lethal, autosomal recessive disorder after cystic fibrosis. Based on the criteria of the Internatinal SMA Consortium, childhood SMAs are classified into type I (Werdnig-Hoffmann Disease), type II (intermediate form), and type III (Kugelberg-Welander Disease). Recently, two genes have been found to be associated with SMA. The survival motor neurone gene (SMN) is an SMA determining gene as it is absent in 98.6% of patients. A second gene, XS2G3, or the highly homologous neuronal apoptosis inhibitory protein gene (NAIP) have been found to be more frequently deleted in type I than in the milder forms (types II and III). We investigated the correlation between the clinical phenotype and the genotype at this loci. A total of 106 patients were classified into type I (44), type II (31), and type III (31) and analysed using SMN, markers C212 and C272, and NAIP mapping upstream and downstream from SMN respectively. The combined analysis of all markers showed a large proportion of type I patients (43%) carried deletions of both SMN and its flanking markers (C212/272) and NAIP exon 5), as compared with none of the patients with type II or III SMA. The presence of large scale deletions involving these loci is specific to Werdnig-Hoffman Disease (type I) and allows one to predict the severity of the Disease in our series.
