SMN1 – Spinal Muscular Atrophy Type III

Spinal muscular atrophy type III (SMA3, Kugelberg–Welander disease) is an autosomal recessive motor neuron disorder characterized by proximal muscle weakness and variable onset in childhood or early adulthood. The causative gene, SMN1, maps to chromosome 5q13.2 and is essential for small nuclear ribonucleoprotein (snRNP) biogenesis. Loss of both SMN1 alleles leads to SMN protein deficiency in motor neurons, while SMN2 copy number modulates disease severity. Genetic testing for SMN1 exon 7 deletion and intragenic mutations underpins diagnostic confirmation and carrier screening.

Genetic evidence for SMN1 in SMA3 includes a case of paternal uniparental isodisomy in a 2-year-old boy with type III SMA, demonstrating autosomal recessive inheritance without maternal contribution ([PMID:8116617]). A cross-sectional study of 23 unrelated adults with SMA3 provided further confirmation of SMN1 pathogenicity through consistent clinical and molecular findings, including exon 7 deletions and intragenic variants ([PMID:39335757]). Additionally, the intronic splice-site variant c.834+6T>G was shown to impair exon 7 inclusion in SMN transcripts, presenting in SMA patients but absent in controls ([PMID:10339583]).

The variant spectrum in SMA3 encompasses homozygous or compound heterozygous SMN1 exon deletions, rare intragenic missense and nonsense mutations, and splice-site alterations. The c.834+6T>G splice variant remains a landmark non-coding change, while recurrent SMN1 exon 7 deletions account for ≥95% of cases. SMN2 copy number correlates inversely with disease severity, with higher SMN2 dosage associated with milder phenotypes.

Functional studies have elucidated the mechanism of SMN1 loss in SMA. Wild-type SMN promotes snRNP assembly and pre-mRNA splicing in vitro, whereas patient-derived mutants fail to support snRNP biogenesis ([PMID:9845364]). In zebrafish models, SMN depletion causes motor axon outgrowth defects that are specifically rescued by full-length SMN but not by SMNΔ7 or SMA-associated point mutants, dissociating snRNP assembly from axonal functions ([PMID:17065443]).

No studies have robustly disputed the SMN1–SMA3 association. The combination of segregation in a uniparental isodisomy case, case series in unrelated adults, and concordant experimental data supports a strong gene–disease relationship.

In summary, SMN1 loss-of-function mutations cause SMA type III through impaired snRNP assembly and motor neuron degeneration. Genetic testing for SMN1 deletions and intragenic variants, along with SMN2 copy-number assessment, enables accurate diagnosis, prognostic stratification, and informs emerging therapies targeting SMN2 splicing. Key Take-home: SMN1 biallelic loss is a strongly validated cause of SMA3, guiding carrier screening, diagnostic workflows, and splicing-modulating treatments.

References

• American journal of human genetics • 1994 • Paternal isodisomy for chromosome 5 in a child with spinal muscular atrophy. [PMID:8116617]
• Proceedings of the National Academy of Sciences of the United States of America • 1999 • A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. [PMID:10339583]
• Diagnostics • 2024 • Glucose and Lipid Metabolism Disorders in Adults with Spinal Muscular Atrophy Type 3. [PMID:39335757]
• Cell • 1998 • A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. [PMID:9845364]
• The Journal of neuroscience • 2006 • Survival motor neuron function in motor axons is independent of functions required for small nuclear ribonucleoprotein biogenesis. [PMID:17065443]

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