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

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 pr...

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Bibliographic Details
Published in:	Neurobiology of disease Vol. 156; p. 105421
Main Authors:	van der Zee, Julie, Dillen, Lubina, Baradaran-Heravi, Yalda, Gossye, Helena, Koçoğlu, Cemile, Cuyt, Ivy, Dermaut, Bart, Sieben, Anne, Baets, Jonathan, De Jonghe, Peter, Vandenberghe, Rik, De Deyn, Peter, Cras, Patrick, Engelborghs, Sebastiaan, Van Broeckhoven, Christine
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-08-2021 Elsevier
Subjects:	Aged Aged, 80 and over Amino Acid Sequence Amyotrophic Lateral Sclerosis - diagnosis Amyotrophic Lateral Sclerosis - epidemiology Amyotrophic Lateral Sclerosis - genetics Amyotrophic lateral sclerosis, ALS Belgium - epidemiology Cohort Studies Exome sequencing Female Frontotemporal Dementia - diagnosis Frontotemporal Dementia - epidemiology Frontotemporal Dementia - genetics Frontotemporal dementia, FTD Genetic Association Studies - methods Humans Male Middle Aged Nerve Tissue Proteins - genetics Neurodegeneration Pedigree RBM45 RNA binding protein RNA-Binding Proteins - genetics TDP-43 proteinopathy Whole Exome Sequencing - methods Belgium Neurodegeneration RNA binding protein Exome sequencing Frontotemporal dementia, FTD RBM45 TDP-43 proteinopathy Amyotrophic lateral sclerosis, ALS
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Summary:	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. •Exome sequencing identified the RBM45 gene as possible novel candidate gene in FTD and ALS.•RBM45 is an RNA binding protein that accumulates in the TDP-43 positive inclusions.•We identified one nonsense mutation in two first-cousins of an affected family.•We identified the same nonsense mutation and two more ultra-rare VUS in unrelated patients.•Loss of nuclear RBM45 may contribute to the disease biology of the FTD-ALS spectrum.
ISSN:	0969-9961 1095-953X
DOI:	10.1016/j.nbd.2021.105421