Molecular analyses of the Cu/Zn superoxide dismutase gene in patients with familial amyotrophic lateral sclerosis (ALS) in Japan

Masashi Aoki, Koji Abe, Yasuto Itoyama

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

1. Amyotrophic lateral sclerosis (ALS) is a degenerative disorder characterized by selective damage to the neural system that mediates voluntary movement. Although the pathophysiologic process of ALS remains unknown, about 5 to 10% of cases are familial. According to genetic linkage studies, the familial ALS (FALS) gene has been mapped on chromosome 21 in some families and recent work identified some different missense mutations in the Cu/Zn superoxide dismutase gene in FALS families. 2. We recently identified five mutations in six FALS families. The mutations identified in our FALS families are H46R, L84V, I104F, S134N, and V148I. The H46R mutation that locates in the active site of Cu/Zn SOD gene is associated with two Japanese families with very slow progression of ALS. On the other hand, the L84V mutation associated with a rapidly progressive loss of motor function with predominant lower motor neuron manifestations. 3. In the family with the V148I, the phenotype of the patient varied very much among the affected members. One case had weakness of the lower extremities at first and died without bulbar paresis. The second case first noticed wasting of the upper limbs with bulbar symptoms, but the third had weakness of upper extremities without developing dysarthria nor dysphagia until death. These mutations account for 50% of all FALS families screened, although Cu/Zn SOD gene mutations are responsible for less than about 13-21% in the western population. 4. Our results indicate that the progression of disease with mutations of Cu/Zn SOD is well correlated with each mutation. The exact mechanism by which the abnormal Cu/Zn SOD molecules selectively affect the function of motor neurons is still unknown.

Original languageEnglish
Pages (from-to)639-647
Number of pages9
JournalCellular and Molecular Neurobiology
Volume18
Issue number6
DOIs
Publication statusPublished - 1998

Fingerprint

Japan
Genes
Mutation
Neurons
Amyotrophic Lateral Sclerosis
Motor Neurons
Chromosomes
Upper Extremity
Chromosomes, Human, Pair 21
Dysarthria
Molecules
Genetic Linkage
Amyotrophic lateral sclerosis 1
Superoxide Dismutase-1
Superoxide Dismutase
Paresis
Missense Mutation
Deglutition Disorders
Disease Progression
Lower Extremity

Keywords

  • Amyotrophic lateral sclerosis
  • Cu/Zn superoxide dismutase
  • Familial
  • Gene
  • Mutation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Biochemistry
  • Cell Biology
  • Genetics

Cite this

Molecular analyses of the Cu/Zn superoxide dismutase gene in patients with familial amyotrophic lateral sclerosis (ALS) in Japan. / Aoki, Masashi; Abe, Koji; Itoyama, Yasuto.

In: Cellular and Molecular Neurobiology, Vol. 18, No. 6, 1998, p. 639-647.

Research output: Contribution to journalArticle

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abstract = "1. Amyotrophic lateral sclerosis (ALS) is a degenerative disorder characterized by selective damage to the neural system that mediates voluntary movement. Although the pathophysiologic process of ALS remains unknown, about 5 to 10{\%} of cases are familial. According to genetic linkage studies, the familial ALS (FALS) gene has been mapped on chromosome 21 in some families and recent work identified some different missense mutations in the Cu/Zn superoxide dismutase gene in FALS families. 2. We recently identified five mutations in six FALS families. The mutations identified in our FALS families are H46R, L84V, I104F, S134N, and V148I. The H46R mutation that locates in the active site of Cu/Zn SOD gene is associated with two Japanese families with very slow progression of ALS. On the other hand, the L84V mutation associated with a rapidly progressive loss of motor function with predominant lower motor neuron manifestations. 3. In the family with the V148I, the phenotype of the patient varied very much among the affected members. One case had weakness of the lower extremities at first and died without bulbar paresis. The second case first noticed wasting of the upper limbs with bulbar symptoms, but the third had weakness of upper extremities without developing dysarthria nor dysphagia until death. These mutations account for 50{\%} of all FALS families screened, although Cu/Zn SOD gene mutations are responsible for less than about 13-21{\%} in the western population. 4. Our results indicate that the progression of disease with mutations of Cu/Zn SOD is well correlated with each mutation. The exact mechanism by which the abnormal Cu/Zn SOD molecules selectively affect the function of motor neurons is still unknown.",
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