ALS Genes in the Genomic Era and their Implications for FTD

Nguyen, Hien; Broeckhoven, Christine Van; Zee, Julie van der

doi:10.1016/j.tig.2018.03.001

Cited by 255 publications

(196 citation statements)

References 155 publications

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“…In this study, we wished to compare HRE C9ORF72 phenotypically and mechanistically against mutant FUS and TDP43, all of which are common genetic aberrations causing ALS (6,7). We sought to combine LOF of C9ORF72 with HRE-mediated GOF in a meaningful manner with no overexpression artifacts to clarify the role of both debated mechanisms (15,16,26,27).…”

Section: Discussionmentioning

confidence: 99%

“…A better understanding of the underlying pathomechanism is hampered by the multitude of genetic causes in familial and sporadic ALS. To date, over 30 distinct mutations have been identified (6,7), ranging from single amino residue substitutions to truncations and intronic HREs. This diversity of affected genes and mutation types seems to contradict the common scheme of MN degeneration and final clinical outcome in ALS and calls for a thorough, comprehensive dissection in clinically relevant models to reveal mutation-specific upstream versus more common downstream mechanisms during the progression of neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

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High content live profiling reveals concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

Kretner

Abo-Rady

et al. 2020

Preprint

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Single sentence summaryPathogenesis in C9ORF72 ALS shows a distinct spatiotemporal axonal organelle trafficking impairment caused by gain and loss of function mechanisms. AbstractIntronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS), a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOF) through DPRs versus loss of C9ORF72 functions (LOF). Through multiparametric HC live profiling in spinal MNs from induced pluripotent stem cells (iPSCs)and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA strand breaks (DSBs), DPRs and apoptosis. We show that both GOF and LOF were necessary to yield the overall C9ORF72 pathology.Finally, C9ORF72 LOF was sufficientalbeit to a smaller extentto induce proximal axonal trafficking deficits and increased DSBs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High content live profiling reveals concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

Kretner

Abo-Rady

et al. 2020

Preprint

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“…First, rare variants in TREM2 confer risk for both AD 61 and FTD 62 . Second, rare variation in multiple established genes such as TBK1 and C9orf72 confer risk or are causative across the ALS-FTD spectrum 63 . Third, moderately penetrant common risk alleles like APOE ε4 are primarily associated with AD, but also associated with risk for Dementia with Lewy Bodies (DLB) 64 , FTD 12 , and age of onset in C9orf72 carriers 65 .…”

Section: Discussionmentioning

confidence: 99%

Non-Coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases

Cochran

Geier

Bonham

et al. 2019

Preprint

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ABSTRACTWe conducted genome sequencing to search for rare variation contributing to early onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 493 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than 1 in 10,000 or private), computational prediction of deleteriousness (CADD 10 or 15 thresholds), and molecular function (protein loss-of-function only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions).Replication analysis was conducted on 16,871 independent cases and 15,941 independent controls. Rare variants in TET2 were enriched in the discovery combined EOAD and FTD cohort (p=6.5×10−8, genome-wide corrected p=0.0037). Most of these variants were canonical loss-of-function or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of AD and FTD (replication only p=0.0071). The combined analysis odds ratio was 2.2 (95% CI 1.5–3.2) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 2.1 (95% CI 1.2–3.9). For loss-of-function variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.2 (95% CI 2.0–5.3). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.

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“…The FTD-ALS causative gene TBK1 contributed to about 1.3% ALS, 3%-4% ALS-FTD, and <1% FTD with TDP-43 pathology (Nguyen, Van Broeckhoven, & van der Zee, 2018), of whom great clinical heterogeneity was presented. Considering the TBK1 variants, clinical manifestations of reported mutations in FTD-ALS spectrum were listed (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Association of the TBK1 mutation p.Ile334Thr with frontotemporal dementia and literature review

Luo

et al. 2019

Molec Gen & Gen Med

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Background The mutation of TANK‐binding kinase 1 ( TBK1 ) gene has been regarded as a causative gene of frontotemporal dementia (FTD)‐amyotrophic lateral sclerosis (ALS) spectrum disease in recent years. So far, more than 70 TBK1 variants have been identified in patients with FTD‐ALS spectrum. Methods We reported a Chinese FTD patient carrying TBK1 p.Ile334Thr variant detected by target sequencing and Sanger sequencing. The patient's clinical materials were collected. The transcription and translation levels of TBK1 mutant were investigated in fibroblast by qPCR and western blot. The effects of TBK1 mutant in inflammation pathway and autophagy were detected by luciferase reporter assay and GST pull‐down assay. Results The patient was diagnosed as behavioral variant FTD (bvFTD) and displayed progressively severe cognitive impairment especially in executive function. A pattern of frontotemporal atrophy and hypometabolism was shown through MRI and PET‐CT. In vitro functional experiments of TBK1 p.Ile334Thr variant demonstrated reduced transcription and translation levels, decreased kinase activity but maintenance of interaction with optineurin. The variant was classified as likely pathogenic according to American College of Medical Genetics and Genomics guideline. Conclusion We proposed the TBK1 mutation p.Ile334Thr as a likely pathogenic variant in bvFTD which also expanded the clinical spectrum of this variant. It can partially abrogate TBK1 functions and be responsible for FTD‐ALS spectrum diseases through neuroinflammatory pathway.

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ALS Genes in the Genomic Era and their Implications for FTD

Cited by 255 publications

References 155 publications

High content live profiling reveals concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

High content live profiling reveals concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

Non-Coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases

Association of the TBK1 mutation p.Ile334Thr with frontotemporal dementia and literature review

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