title: SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS.
abstract: BACKGROUND
  ALS is believed to be multifactorial in origin with modifying genes affecting its clinical expression. Childhood-onset spinal muscular atrophy (SMA) is an autosomal recessive disorder of motor neurons, caused by mutations of the survival motor neuron (SMN) gene. The SMN gene exists in two highly homologous variants: SMN1, the causative gene responsible for the production of the majority of functional SMN protein, and SMN2, responsible for the production of less protein but sufficient for modifying the SMA phenotype.
  
  
  OBJECTIVE
  To test whether SMN genotypes are associated with susceptibility to and severity of sporadic ALS.
  
  
  METHODS
  We performed competitive quantitative PCR analysis for both SMN1 and SMN2 genes in 242 clinically well-defined ALS patients and 175 controls. The combined determination of SMN1 and SMN2 copies also allowed for an estimation of the level of SMN for each patient (estimated SMN protein level = SMN1 copy number + 0.20 x SMN2 copy number).
  
  
  RESULTS
  One copy of SMN1 was associated with an increased risk of developing ALS (odds ratio = 4.1, 95% CI = 1.2 to 14.2, p = 0.02) and ALS patients carried fewer SMN2 copy numbers (p < 0.001). Sixty-one percent of patients had an estimated protein SMN level < or = 2.2 vs only 36% of controls (p = 0.0000004). Multivariate Cox regression analyses showed that lower SMN2 copy numbers and lower levels of estimated SMN protein (hazard ratio = 1.3, 95% CI = 1.1 to 1.6, p = 0.03) were associated with an increased mortality rate.
  
  
  CONCLUSIONS
  SMN genotypes producing less SMN protein increase susceptibility to and severity of ALS.
authors.affiliation: Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Veldink
authors.forename: S
authors.initials: S
authors.lastname: Kalmijn
authors.forename: A H
authors.initials: AH
authors.lastname: Van der Hout
authors.forename: H H
authors.initials: HH
authors.lastname: Lemmink
authors.forename: G J
authors.initials: GJ
authors.lastname: Groeneveld
authors.forename: C
authors.initials: C
authors.lastname: Lummen
authors.forename: H
authors.initials: H
authors.lastname: Scheffer
authors.forename: J H J
authors.initials: JH
authors.lastname: Wokke
authors.forename: L H
authors.initials: LH
authors.lastname: Van den Berg
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D002470:Cell Survival / Q000235:genetics; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015331:Cohort Studies; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency* / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D055532:SMN Complex Proteins; D012720:Severity of Illness Index; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein