Family-based exome sequencing identifies RBM45 as a possible candidate gene for frontotemporal dementia and amyotrophic lateral sclerosis

Neurobiol Dis. 2021 Aug:156:105421. doi: 10.1016/j.nbd.2021.105421. Epub 2021 Jun 9.


Neurodegenerative disorders like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are pathologically characterized by toxic protein deposition in the cytoplasm or nucleus of affected neurons and glial cells. Many of these aggregated proteins belong to the class of RNA binding proteins (RBP), and, when mutated, account for a significant subset of familial ALS and FTD cases. Here, we present first genetic evidence for the RBP gene RBM45 in the FTD-ALS spectrum. RBM45 shows many parallels with other FTD-ALS associated genes and proteins. Multiple lines of evidence have demonstrated that RBM45 is an RBP that, upon mutation, redistributes to the cytoplasm where it co-aggregates with other RBPs into cytoplasmic stress granules (SG), evolving to persistent toxic TDP-43 immunoreactive inclusions. Exome sequencing in two affected first cousins of a heavily affected early-onset dementia family listed a number of candidate genes. The gene with the highest pathogenicity score was the RBP gene RBM45. In the family, the RBM45 Arg183* nonsense mutation co-segregated in both affected cousins. Validation in an unrelated patient (n = 548) / control (n = 734) cohort identified an additional RBM45 Arg183* carrier with bvFTD on a shared 4 Mb haplotype. Transcript and protein expression analysis demonstrated loss of nuclear RBM45, suggestive of a loss-of-function disease mechanism. Further, two more ultra-rare VUS, one in the nuclear localization signal (NLS, p.Lys456Arg) in an ALS patient and one in the intrinsically disordered homo-oligomer assembly (HOA) domain (p.Arg314Gln) in a patient with nfvPPA were detected. Our findings suggest that the pathomechanisms linking RBM45 with FTD and ALS may be related to its loss of nuclear function as a mediator of mRNA splicing, cytoplasmic retention or its inability to form homo-oligomers, leading to aggregate formation with trapping of other RBPs including TDP-43, which may accumulate into persisted TDP-43 inclusions.

Keywords: Amyotrophic lateral sclerosis, ALS; Exome sequencing; Frontotemporal dementia, FTD; Neurodegeneration; RBM45; RNA binding protein; TDP-43 proteinopathy.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / epidemiology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Belgium / epidemiology
  • Cohort Studies
  • Exome Sequencing / methods*
  • Female
  • Frontotemporal Dementia / diagnosis
  • Frontotemporal Dementia / epidemiology
  • Frontotemporal Dementia / genetics*
  • Genetic Association Studies / methods*
  • Humans
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Pedigree
  • RNA-Binding Proteins / genetics*


  • Nerve Tissue Proteins
  • RBM45 protein, human
  • RNA-Binding Proteins