SomaticTARDBPvariants as a cause of semantic dementia

Abstract

The aetiology of late-onset neurodegenerative diseases is largely unknown. Here we investigated whether de novo somatic variants for semantic dementia can be detected, thereby arguing for a more general role of somatic variants in neurodegenerative disease. Semantic dementia is characterized by a non-familial occurrence, early onset (<65 years), focal temporal atrophy and TDP-43 pathology. To test whether somatic variants in neural progenitor cells during brain development might lead to semantic dementia, we compared deep exome sequencing data of DNA derived from brain and blood of 16 semantic dementia cases. Somatic variants observed in brain tissue and absent in blood were validated using amplicon sequencing and digital PCR. We identified two variants in exon one of the TARDBP gene (L41F and R42H) at low level (1–3%) in cortical regions and in dentate gyrus in two semantic dementia brains, respectively. The pathogenicity of both variants is supported by demonstrating impaired splicing regulation of TDP-43 and by altered subcellular localization of the mutant TDP-43 protein. These findings indicate that somatic variants may cause semantic dementia as a non-hereditary neurodegenerative disease, which might be exemplary for other late-onset neurodegenerative disorders.

Primary progressive aphasia and motor neuron disease: A review

“…Also C-terminal missense mutations in the TARDBP gene were detected as a relatively frequent genetic underpinning of PPA-MND (29.4%), although with a disproportion toward SD (80%; PNFA: 20%) – this last finding being in line with several reports ( Gelpi et al, 2014 ; González-Sánchez et al, 2018 ), also showing that SD is overrepresented in TARDBP carriers compared to other FTD phenotypes ( Caroppo et al, 2016 ; van Rooij et al, 2020 ).…”

Neurocognitive patterns across genetic levels in behavioral variant frontotemporal dementia: a multiple single cases study

“…Classical reports of FTD-TARDBP revealed a diffuse pattern of atrophy affecting temporal, orbitofrontal, and cingulate cortices in FTD patients associated with cognitive and semantic deficits [ 45 , 85 , 98 , 99 ]. Our work shown an even more extended pattern of atrophy beyond classical frontal, temporal, cingulated regions, extending to the precuneus, parahippocampal cortex, cerebellum, and sensory cortex.…”

“…TARDBP mutations present with frontotemporal atrophy are associated with behavioral disturbances, including disinhibition [ 39 , 44 ]. Presentations with semantic variant primary progressive aphasia have been also reported [ 45 ]. Finally, in this group, we also included one patient with a mutation in the gene encoding the Triggering Receptor Expressed on Myeloid cells 2 ( TREM2 ), a significant regulator of neuroinflammatory processes in neurodegeneration [ 11 , 12 , 46 ], that are also associated with familial forms of FTD.…”

Brain somatic mutations as RNA therapeutic targets in neurological disorders

“…Somatic copy number increases in SNCA (encoding α‐synuclein) have been observed in nigral dopaminergic neurons in Parkinson's disease 82 . Somatic SNVs in TARDBP , encoding TDP‐43, the major pathological protein aggregate in ALS, were reported to be causal of semantic dementia 83 . However, like somatic mutations in neuropsychiatric disorders, current studies do not yet support the causality of brain somatic mutations in neurodegenerative disorders.…”