Genetic Cause

SMA story I

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SMA story II

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Please note, throughout this website, when discussing “SMA”, we are referring to 5q SMA, the most common form of the disease.

In healthy individuals, SMN1 is the primary producer of functional, full-length SMN protein;²
In individuals with SMA, the missing SMN1 gene results in levels of functional, full-length SMN protein that are insufficient to sustain the survival of motor neurons;^2-5
At the time of the discovery of the SMN1 gene, a duplicate gene, now known as SMN2, was also found.⁶

Functional, full-length SMN protein is necessary to maintain the health and function of motor neurons in the spinal cord.⁵

Arrow indicates a healthy motor neuron.
With permission from Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371(9630):2120-2133.

SMN1 is different to SMN2 by only 5 nucletide base pairs. This variation leads to the exclusion of exon 7 in most SMN2 pre-messenger ribonucleic acid (pre-mRNA) transcripts;⁵
The difference between SMN1 and SMN2 lies within SMN protein; the SMN2 gene produces only ≈10% functional, full-length SMN protein.⁵

SMN2 produces pre-mRNA transcripts that mostly exclude exon 7, resulting in low levels of functional SMN protein.¹

The level of functional SMN protein produced by SMN2 is insufficient to compensate for the missing or mutated SMN1 gene in individuals with SMA.^5,7

SMN2 has the capacity to produce functional, full-length SMN protein.⁵

How does untreated SMA manifest?

Learn more about the natural history of untreated SMA.

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SMN=survival motor neuron

References

Darras BT, Royden Jones H Jr, Ryan MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. 2nd ed. London, UK: Elsevier; 2015.
Rochette CF, Gilbert N, Simard LR. SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Hum Genet. 2001;108:255-266.
Butchbach ME. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci. 2016;3:7.
Jablonka S, Schrank B, Kralewski M, Rossoll W, Sendtner M. Reduced survival motor neuron (Smn) gene dose in mice leads to motor neuron degeneration: an animal model for spinal muscular atrophy type III. Hum Molec Genet. 2000;9(3):341-346.
Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371(9630):2120-2133.
Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-165.
Mitrpant C, Porensky P, Zhou H, et al. Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy. PLOS One. 2013;8(4):e62114.
Monani UR. Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron. 2005;48(6):885-896.

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