Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?

Burghes, Arthur H.M.; Beattie, Christine E.

doi:10.1038/nrn2670

Cited by 620 publications

(662 citation statements)

References 169 publications

(196 reference statements)

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“…Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders and the most common genetic cause of infant mortality [1][2][3]. SMA is caused by loss of the survival of motoneuron (SMN) protein, resulting in the degeneration of alpha motoneurons in spinal cord.…”

Section: Introductionmentioning

confidence: 99%

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

et al. 2011

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Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders in humans and is a common genetic cause of infant mortality. The disease is caused by loss of the survival of motoneuron (SMN) protein, resulting in the degeneration of alpha motoneurons in spinal cord and muscular atrophy in the limbs and trunk. One function of SMN involves RNA splicing. It is unclear why a deficiency in a housekeeping function such as RNA splicing causes profound effects only on motoneurons but not on other cell types. One difficulty in studying SMA is the scarcity of patient's samples. The discovery that somatic cells can be reprogrammed to become induced pluripotent stem cell (iPSCs) raises the intriguing possibility of modeling human diseases in vitro. We reported the establishment of five iPSC lines from the fibroblasts of a type 1 SMA patient. Neuronal cultures derived from these SMA iPSC lines exhibited a reduced capacity to form motoneurons and an abnormality in neurite outgrowth. Ectopic SMN expression in these iPSC lines restored normal motoneuron differentiation and rescued the phenotype of delayed neurite outgrowth. These results suggest that the observed abnormalities are indeed caused by SMN deficiency and not by iPSC clonal variability. Further characterization of the cellular and functional deficits in motoneurons derived from these iPSCs may accelerate the exploration of the underlying mechanisms of SMA pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

et al. 2011

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“…It has been hypothesized that the inability of SMND7 protein to oligomerize, coupled with the resulting reduction in interactions with its own partners, might be responsible for the instability of this isoform [Lorson et al, 1998]. However, because SMN is part of a very large multimeric complex, it is possible that SMND7 is stabilized in vivo due to its association with other proteins in the complex [Burghes and Beattie, 2009]. In favor of this hypothesis is the observation that expression of the SMND7 isoform in a Smn À/À ; SMN2 þ/þ background dramatically improves the survival of a severe mouse model of the disease [Le et al, 2005].…”

Section: Smn: How Many Functions Can a Single Protein Possess?mentioning

confidence: 99%

“…T transition at position þ6 of exon 7 of SMN2 [Monani et al, 1999;Lorson et al, 1999] which disrupts interactions of the pre-mRNA with splicing enhancer and silencer proteins such that SMN2 transcripts predominantly exclude exon 7 (SMND7) Cartegni and Krainer, 2002;Hofmann and Wirth, 2002;Kashima and Manley, 2003;Singh et al, 2006;Chen et al, 2008;Gladman and Chandler, 2009]. SMN2 genes do not produce sufficient full length SMN protein to prevent the onset of the disease but, on the other hand, because each SMN2 gene can produce a small amount of full length SMN transcripts, no patient is devoid of SMN protein and disease severity is dependent on the amount of residual SMN protein [reviewed in Burghes and Beattie, 2009]. Deletions, most often associated with type I SMA, result in a drastic reduction in SMN protein [Lefebvre et al, 1995;Coovert et al, 1997].…”

Section: Introductionmentioning

confidence: 99%

“…Deletions, most often associated with type I SMA, result in a drastic reduction in SMN protein [Lefebvre et al, 1995;Coovert et al, 1997]. Patients with Type II-IV SMA can have SMN2-like genes at the SMN1 locus and thus often possess three or four copies of SMN2 genes [Hahnen et al, 1996;van der Steege et al, 1996;Velasco et al, 1996;Burghes, 1997;DiDonato et al, 1997] capable of contributing variable amounts of functional and semi-functional SMN complexes [Lefebvre et al, 1995;Coovert et al, 1997;Burghes and Beattie, 2009] and modify disease presentation. Not surprisingly, disease severity correlates with SMN2 gene copy number, although this correlation is not absolute [Burghes, 1997;Vitali et al, 1999;Feldkotter et al, 2002;Tiziano et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

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Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

Tiziano

Melki

Simard

2013

American J of Med Genetics Pt A

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Spinal muscular atrophy (SMA) is an autosomal recessive, lower motor neuron disease. Clinical heterogeneity is pervasive: three infantile (type I-III) and one adult-onset (type IV) forms are recognized. Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA. Most forms of SMA are caused by mutations of the survival motor neuron (SMN1) gene. A second gene that is 99% identical to SMN1 (SMN2) is located in the same region. The only functionally relevant difference between the two genes identified to date is a C ! T transition in exon 7 of SMN2, which determines an alternative spliced isoform that predominantly excludes exon 7. Thus, SMN2 genes do not produce sufficient full length SMN protein to prevent the onset of the disease. Since the identification of the causative mutation, biomedical research of SMA has progressed by leaps and bounds: from clues on the function of SMN protein, to the development of different models of the disease, to the identification of potential treatments, some of which are currently in human trials. The aim of this review is to elucidate the current state of knowledge, emphasizing how close we are to the solution of the puzzle that is SMA, and, more importantly, to highlight the missing pieces of this puzzle. Filling in these gaps in our knowledge will likely accelerate the development and delivery of efficient treatments for SMA patients and be a prerequisite towards achieving our final goal, the cure of SMA. Ó 2013 Wiley Periodicals, Inc. Key words: spinal muscular atrophy; SMN INTRODUCTIONSpinal muscular atrophy (SMA) is a lower motor neuron disease that predominantly affects spinal cord anterior horn cells and brain stem nuclei [Dubowitz, 1995; reviewed in Hamilton and Gillingwater, 2013]. Alpha-motor neuron cell degeneration results in progressive, symmetrical skeletal muscle atrophy of limbs and trunk, spreading proximal to distal [Crawford and Pardo, 1996]. Clinical heterogeneity is pervasive: based on the age of onset and on the maximum motor achievement of patients, three infantile (type I-III) and one adult-onset (type IV) forms are commonly recognized. Classification criteria are summarized in Table I. However, this rigid classification does not accurately depict the range of SMA clinical phenotypes, which display a more continuous spectrum, ranging from prenatal onset to almost asymptomatic patients. SMA is a common autosomal recessive disorder (incidence is $1 in 6,000 in most ethnicities). Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA [Crawford and Pardo, 1996;Prior, 2010].Most forms of SMA are caused by mutations in the survival motor neuron (SMN) gene, which was isolated in 1995 in chromosome 5q13 harboring a segmental duplication [Lefebvre et al., 1995]. Mutations in SMN1 are responsible for the four forms of SMA [Wirth, 2000;Alías et al., 2009]. A second gene that is 99% identical to SMN1, the SMN2 gene, is located in the same region [Le...

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“…produced is a protein that is truncated and unstable (SMN∆7) and is rapidly degraded (Figure 1). 10,15,17,18 Another important point that should be highlighted is that the number of intact copies of SMN 2 is a determinant of disease severity. Figure 2 illustrates the genotype of people who are affected and unaffected by SMA, characterizing type I, II and III patients.…”

Section: Classification Of Smamentioning

confidence: 99%

Atrofia muscular espinhal: diagnóstico, tratamento e perspectivas futuras

Baioni¹,

Ambiel²

2010

J. Pediatr. (Rio J.)

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Objective: To report on recent genetic and molecular discoveries and on future prospects for the treatment of spinal muscular atrophy (SMA), thereby helping healthcare professionals to make a quick diagnosis and provide appropriate and timely therapeutic support.Sources: Information was collected from scientific articles published in the last 2 decades, retrieved from the databases SciELO, PubMed, and MEDLINE. Summary of the findings:SMA is a neurodegenerative disorder with autosomal recessive genetic heredity. It is caused by a homozygous deletion of the survival motor neuron (SMN 1 ) gene. This genetic alteration results in reduced levels of the SMN protein, leading to degeneration of alpha motor neurons of the spinal cord and resulting in muscle weakness and progressive symmetrical proximal paralysis. It is known that basic nutritional and respiratory care and physiotherapy can be important to delaying disease progression and prolonging patients' lives. Several drugs are being tested, some new, others, such as valproic acid, already known; paralysis can be halted, but not reversed. Conclusions:SMA is a difficult to diagnose disorder, because it is little known, and treatment is uncertain. Pharmacological treatments and supportive therapies are not yet able to recover motor neurons or muscle cells that have already been lost, but are aimed at delaying disease progression and improving patients' residual muscle function, as well as offering better quality of life and life expectancy.

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Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?

Cited by 620 publications

References 169 publications

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

Atrofia muscular espinhal: diagnóstico, tratamento e perspectivas futuras

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