Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q1 1.2–13.3

Brzustowicz, Linda M.; Lehner, Thomas; Castilla, Lucio H.; Penchaszadeh, Graciela K.; Wilhelmsen, Kirk C.; Daniels, R. J.; Davies, Kay E.; Leppert, M.; Ziter, Fred A.; Wood, Douglas; Dubowitz, Victor; Zerres, Klaus; Hausmanowa-Pétrusewicz, I; Ott, Jürg; Munsat, Theodore L.; Gilliam, T. Conrad

doi:10.1038/344540a0

Cited by 529 publications

(192 citation statements)

References 17 publications

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“…Over 98% of SMA patients have mutations or deletions of the Survival Motor Neuron (SMN1) gene, which is present as an inverted repeat on chromosome 5 at 5q13 (5)(6)(7). Only deletions or mutations in the telomeric copy of SMN (SMN1) lead to SMA (7)(8)(9)(10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

Specific Sequences of the Sm and Sm-like (Lsm) Proteins Mediate Their Interaction with the Spinal Muscular Atrophy Disease Gene Product (SMN)

Friesen

Dreyfuss

2000

Journal of Biological Chemistry

123

112

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The spinal muscular atrophy disease gene product (SMN) is crucial for small nuclear ribonuclear protein (snRNP) biogenesis in the cytoplasm and plays a role in pre-mRNA splicing in the nucleus. SMN oligomers interact avidly with the snRNP core proteins SmB, -D1, and -D3. We have delineated the specific sequences in the Sm proteins that mediate their interaction with SMN. We show that unique carboxyl-terminal arginine-and glycine-rich domains comprising the last 29 amino acids of SmD1 and the last 32 amino acids of SmD3 are necessary and sufficient for SMN binding. Interestingly, SMN also interacts with at least two of the U6-associated Sm-like (Lsm) proteins, Lsm4 and Lsm6. Furthermore, the carboxyl-terminal arginine-and glycine-rich domain of Lsm4 directly interacts with SMN. This suggests that SMN also functions in the assembly of the U6 snRNP in the nucleus and in the assembly of other Lsm-containing complexes. These findings demonstrate that arginineand glycine-rich domains are necessary and sufficient for SMN interaction, and they expand further the range of targets of the SMN protein.Spinal muscular atrophy (SMA) 1 is a neuromuscular disease that results in muscular weakness and atrophy due to degeneration of motor neurons of the spinal cord (1-4). Over 98% of SMA patients have mutations or deletions of the Survival Motor Neuron (SMN1) gene, which is present as an inverted repeat on chromosome 5 at 5q13 (5-7). Only deletions or mutations in the telomeric copy of SMN (SMN1) lead to SMA (7)(8)(9)(10)(11)(12)(13)(14). The centromeric copy of the gene (SMN2) produces mostly an alternatively spliced form of SMN deleted of amino acids encoded by exon 7 (SMN⌬Ex7), and SMN2 can only partially compensate for mutations or deletions in SMN1 (7,15,16). Indeed, some patients, instead of complete deletion of SMN1, have shorter deletions of at least exon 7 or single point mutations within the conserved YG domain (17,18).As measured by coimmunoprecipitation from cytoplasmic extracts, SMN exists in a complex with Sm proteins (19), Gemin2 (formerly SIP1) (19), Gemin4 (20), and the DEAD box RNA helicase Gemin3 (21). The amino terminus of SMN tightly associates with Gemin2, whereas the carboxyl-terminal conserved YG domain is necessary for self-association and interaction with the core snRNP Sm proteins (19,22). We have recently demonstrated that oligomerization of SMN through the conserved YG domain is required for efficient interaction with SmB, -D1, and -D3 and suggested that upon oligomerization a high affinity Sm protein binding site is formed (23).SnRNPs are formed in the cytoplasm where the core Sm proteins bind to the Sm site on U snRNA, and following hypermethylation of the m 7 G cap to a 2,2,7-trimethyl-gaunosine (m 3 G) cap the snRNP is transported to the nucleus (24 -30). Using oocyte injections, it was demonstrated that the SMN⅐Gemin2 complex plays a role in spliceosomal snRNP assembly that takes place in the cytoplasm. Injection of Gemin2-specific monoclonal antibodies inhibited, whereas injection of SMN-specifi...

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confidence: 99%

Specific Sequences of the Sm and Sm-like (Lsm) Proteins Mediate Their Interaction with the Spinal Muscular Atrophy Disease Gene Product (SMN)

Friesen

Dreyfuss

2000

Journal of Biological Chemistry

123

112

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“…SMA III (Kugelberg-Weiander) is a more benign form which becomes evident in late childhood or adolescence 115,22 . In spite of this heterogeneity all of the different forms are caused by the same genetic error on chromosome 5 (5q) 3,l \ It is certain that most, if not all, of the patients with SMA have a progressive motor deterioration, in spite of conventional physiotherapic treatment 4 .…”

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confidence: 99%

Spinal muscular atrophy type II (intermediary) and III (Kugelberg-Welander): evolution of 50 patients with physiotherapy and hydrotherapy in a swimming pool

Cunha

Oliveira

Labronici

et al. 1996

Arq. Neuro-Psiquiatr.

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-We added hydrotherapy to 50 patients with spinal muscular atrophy (SMA) who were being treated with individual conventional physiotherapy. Hydrotherapy was performed at an approximate temperature of 30 degrees Celsius, twice a week, for thirty minutes in children and for forty-five minutes in adults during a 2-year period. The outcome derived from this combined modality of treatment was rated according to physiotherapeutic evaluations, the MMT (Manual Muscular Test), and the Barthel Ladder. Patients were reevaluated at 2-month intervals. After two years of ongoing treatment, we were able to observe that the deformities in hip, knee and foot were progressive in all SMA Type II patients, and in some Type III. Muscle strength stabilized in most SMA Type III patients, and improved in some. MMT was not done in SMA Type II. In all patients we were able to detect an improvement in the Barthel Ladder scale. This study suggests that a measurable improvement in the quality of daily living may be obtained in patients with SMA Types II and III subjected to conventional physiotherapy when associated with hydrotherapy.KEY WORDS: physiotherapy, hydrotherapy, spinal muscular atrophy.Spinal muscular atrophy (SMA) manifests as diffuse muscle weakness secondary to degeneration of the anterior horn cells and bulbar nuclei without pyramidal tract involvement 5,6,7 . Atrofia muscular espinhal tipo II (intermediária) e III (Kugelberg-Welander): evolução de 50 pacientes com fisioterapia e hidroterapia em piscinaRESUMO -A hidroterapia foi realizada em SO pacientes com atrofia muscular espinhal, os quais foram também tratados com fisioterapia individual convencional. O tratamento hidroterápico foi realizado em piscina aquecida numa temperatura de aproximadamente 30° Celsius, duas vezes por semana, durante 30 minutos em crianças e 45 minutos em adultos num período de dois anos. Os benefícios deste tipo de tratamento foram avaliados de acordo com a evolução clínica, o MMT(Teste de Força Muscular) e a Escala de Barthel. Os pacientes foram reavaliados a cada dois meses. Após dois anos de tratamento nós observamos que as deformidades nos quadris, joelhos e pés foram progressivas em todos os pacientes do Tipo II e em alguns do Tipo III. Houve estabilização da força muscular na maioria dos pacientes com SMA Tipo III, e melhora da força em alguns; nos pacientes com SMA Tipo II este teste não pode ser realizado. Em todos os pacientes pudemos verificar melhora em realção à Escala de Barthel. Este estudo sugere que houve melhora destes pacientes com SMA Tipos II e III em relação as atividades de vida diária quando a fisioterapia convencional foi associada a hidroterapia. PALAVRAS-CHAVES: fisioterapia, hidroterapia, atrofia muscular espinhal.

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“…Human chromosome 5 contains such an area at 5q13-14, where the abundance of low-copy repeats has been well documented (4)(5)(6)(7)(8)(9). Interestingly, the gene for spinal muscular atrophy (SMA) has been mapped in tight linkage to this region (10,11).…”

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Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene.

Selig

Bruno

Scharf

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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Low-copy repeats have been associated with genomic rearrangements and have been implicated in the generation of mutations in several diseases. Here we characterize a subset of low-copy repeats in the spinal muscular atrophy (SMA) region in human chromosome 5q13. We show that this repeated sequence, named c41-cad, is a highly expressed pseudogene derived from an intact neuronal cadherin gene, Br-cadherin, situated on Spl3-14. Br-cadherin is expressed specifically in the brain, whereas the c41-cad transcripts are 10-15 times more abundant and are present in all tissues examined. We speculate that the c41-cad repeats, separately or in concert with other repeats in the SMA region, are involved in the pathogenesis of SMA by promoting rearrangements and deletions.

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Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q1 1.2–13.3

Cited by 529 publications

References 17 publications

Specific Sequences of the Sm and Sm-like (Lsm) Proteins Mediate Their Interaction with the Spinal Muscular Atrophy Disease Gene Product (SMN)

Specific Sequences of the Sm and Sm-like (Lsm) Proteins Mediate Their Interaction with the Spinal Muscular Atrophy Disease Gene Product (SMN)

Spinal muscular atrophy type II (intermediary) and III (Kugelberg-Welander): evolution of 50 patients with physiotherapy and hydrotherapy in a swimming pool

Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene.

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