Research Findings

2024.11.06

SMN2 gene copy number affects the incidence and prognosis of motor neuron diseases in Japan

▶ BMC Med Genomics 17, 263 (2024). https://doi.org/10.1186/s12920-024-02026-y

Ishihara T1,2*, Koyama A3, Atsuta N4, Tada M5, Toyoda S1, Kashiwagi K1, Hirokawa S1, Hatano Y1, Yokoseki A1, Nakamura R4, Tohnai G6, Izumi Y7, Kaji R7, Morita M8, Tamura A9, Kano O10, Aoki M11, Kuwabara S12, Kakita A5, Sobue G6,13 and Onodera O1

  1. Department of Neurology, Brain Research Institute, Niigata University
  2. Advanced Treatment of Neurological Diseases Branch, Brain Research Institute, Niigata University
  3. Division of Legal Medicine, Graduate School of Medicine and Dental Science, Niigata University
  4. Department of Neurology, Aichi Medical University School of Medicine
  5. Department of Pathology, Brain Research Institute, Niigata University
  6. Division of ALS Research, Aichi Medical University School of Medicine
  7. Department of Neurology, Tokushima University Graduate School of Biomedical Sciences
  8. Division of Neurology, Department of Internal Medicine, Jichi Medical University
  9. Department of Neurology, Mie University Graduate School of Medicine
  10. Department of Neurology, Toho University Faculty of Medicine
  11. Department of Neurology, Tohoku University Graduate School of Medicine
  12. Department of Neurology, Graduate School of Medicine, Chiba University
  13. Aichi Medical University

Abstract

Background: The copy number status (CNS) of the survival motor neuron (SMN) gene may influence the risk and prognosis of amyotrophic lateral sclerosis (ALS) and lower motor neuron diseases (LMND) other than spinal muscular atrophy (SMA). However, previous studies of this association, mainly from Europe, have yielded controversial results, suggesting possible regional differences. Here, we investigated the effect of the SMN gene in Japanese patients with ALS and LMND.

Methods: We examined the SMN copy numbers and clinical histories of 487 Japanese patients with sporadic ALS (281 men; mean age at onset 61.5 years), 50 with adult LMND (50 men; mean age at onset 58.4 years) and 399 Japanese controls (171 men; mean age 62.2 years). Patients with pathogenic mutations in ALS-causing genes were excluded. SMN1 and SMN2 copy numbers were determined using the droplet digital polymerase chain reaction.

Results: The frequency of a copy number of one for the SMN2 gene was higher in patients with ALS (38.0%) than in healthy controls (30.8%) (odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.04-1.82, p < 0.05). The SMN2 copy number affected the survival time of patients with ALS (median time: 0 copies, 34 months; 1 copy, 39 months; 2 copies, 44 months; 3 copies, 54 months; log-rank test, p < 0.05). Cox regression analysis revealed that the SMN2 copy number was associated with increased mortality (hazard ratio = 0.84, 95% CI = 0.72-0.98, p < 0.05). Also, null SMN2 cases were significantly more frequent in the LMND group (12.0%) than in the control group (4.8%) (OR = 2.73, 95% CI = 1.06-6.98, p < 0.05).

Conclusions: Our findings suggest that SMN2 copy number reduction may adversely affect the onset and prognosis of MND, including ALS and LMND, in Japanese.

Keywords: ALS, SMA, LMND, SMN, Copy number status

*Reprinted under a CC BY NC ND 4.0 license.

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