Novel TARDBP missense mutation caused familial amyotrophic lateral sclerosis with frontotemporal dementia and parkinsonism

Neurobiol Aging. 2021 Nov;107:168-173. doi: 10.1016/j.neurobiolaging.2021.05.017. Epub 2021 Jun 1.


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that predominately involves the motor neurons in the brain and spinal cord. The TARDBP gene, encoding TAR DNA-binding protein 43 (TDP-43) protein, has been identified as a major causative gene in ALS. In this study, we screened 275 SALS patients and 20 unrelated FALS probands for TARDBP mutations. We identified three TARDBP mutations in three SALS patients and two TARDBP mutations in two FALS probands, including a previously unreported mutation, p.K176I, in FALS patients consistent with frontotemporal dementia (FTD) and parkinsonism. The p.K176I mutation is the first mutation outside exon 6 of the TARDBP gene manifesting parkinsonism and the first TARDBP mutation manifesting parkinsonism identified in the Chinese population. Our results support that TARDBP mutations are one of the most common changes in both FALS and SALS in China. Patients with TARDBP mutations may have a broad phenotype spectrum of ALS, FTD, and parkinsonism. The TARDBP gene should be included in genetic screening for ALS with FTD, and/or parkinsonism.

Keywords: Amyotrophic lateral sclerosis; Parkinson's disease; TARDBP; frontotemporal dementia; mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / complications
  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / genetics*
  • Asian People / genetics
  • China
  • DNA-Binding Proteins / genetics*
  • Female
  • Frontotemporal Dementia / complications
  • Frontotemporal Dementia / diagnosis
  • Frontotemporal Dementia / genetics*
  • Genetic Association Studies
  • Genetic Testing
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense / genetics*
  • Parkinsonian Disorders / complications
  • Parkinsonian Disorders / diagnosis
  • Parkinsonian Disorders / genetics*


  • DNA-Binding Proteins
  • TARDBP protein, human