Genotype-phenotype relationships in familial amyotrophic lateral sclerosis with FUS/TLS mutations in Japan

Muscle Nerve. 2016 Sep;54(3):398-404. doi: 10.1002/mus.25061. Epub 2016 Feb 23.


Introduction: We investigated possible genotype-phenotype correlations in Japanese patients with familial amyotrophic lateral sclerosis (FALS) carrying fused in sarcoma/translated in liposarcoma (FUS/TLS) gene mutations.

Methods: A consecutive series of 111 Japanese FALS pedigrees were screened for copper/zinc superoxide dismutase 1 (SOD1) and FUS/TLS gene mutations. Clinical data, including onset age, onset site, disease duration, and extramotor symptoms, were collected.

Results: Nine different FUS/TLS mutations were found in 12 pedigrees. Most of the patients with FUS/TLS-linked FALS demonstrated early onset in the brainstem/upper cervical region, and relatively short disease duration. A few mutations exhibited phenotypes that were distinct from typical cases. Frontotemporal dementia was present in 1 patient.

Conclusions: This study revealed a characteristic phenotype in FUS/TLS-linked FALS patients in Japan. FUS/TLS screening is recommended in patients with FALS with this phenotype. Muscle Nerve 54: 398-404, 2016.

Keywords: amyotrophic lateral sclerosis; frontotemporal dementia; fused in sarcoma/translated in liposarcoma; genetic predisposition to disease; phenotype; prospective studies.

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • C9orf72 Protein
  • Cell Cycle Proteins / genetics
  • DNA-Binding Proteins / genetics
  • Family Health*
  • Female
  • Genetic Association Studies*
  • Genotype
  • Humans
  • Japan
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Phenotype
  • Profilins / genetics
  • Proteins / genetics
  • RNA-Binding Protein FUS / genetics*
  • Superoxide Dismutase-1 / genetics
  • Valosin Containing Protein
  • Young Adult


  • C9orf72 Protein
  • C9orf72 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Profilins
  • Proteins
  • RNA-Binding Protein FUS
  • SOD1 protein, human
  • TARDBP protein, human
  • Superoxide Dismutase-1
  • Adenosine Triphosphatases
  • Valosin Containing Protein