<i>TBK1</i>mutations in Italian patients with amyotrophic lateral sclerosis: genetic and functional characterisation

Pozzi, Laura; Valenza, F.; Mosca, Lorena; Mas, Andrea Dal; Domi, Teuta; Romano, Alessandro; Tarlarini, Claudia; Falzone, Yuri Matteo; Tremolizzo, Lucio; Sorarù, Gian Domenico; Cerri, Federica; Ferraro, Pilar M.; Basaia, Silvia; Fazio, Raffaella; Comola, M.; Comi, Giancarlo; Ferrari, Maurizio; Quattrini, Angelo; Lunetta, Christian; Penco, Silvana; Bonanomi, Dario; Carrera, Paola; Riva, Nilo

doi:10.1136/jnnp-2017-316174

Cited by 44 publications

(30 citation statements)

References 31 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we screened a Chinese cohort of 270 cases with ALS, FTD, FTD-ALS (or ALS-FTD) for TBK1 mutations and identified two novel frame-shift TBK1 mutations (p.E653fs and p.L688Rfs*14) in a sporadic case with SD-ALS and an ALS-FTD family respectively, accounting for 0.7% of total cases, which were consistent with the recent Asian population studies from Taiwan (0.5%; 1/207 ALS) and China (0.7%; 2/294 ALS) [ 17 , 18 ], although they were significantly lower than European cohorts, such as Italian (3.2%; 5/154 ALS) and Belgian (1.7% 11/629 ALS, FTD, FTD-ALS) [ 19 , 20 ]. Our results further indicated that the TBK1 gene was not a common gene in the Chinese population.…”

Section: Discussionsupporting

confidence: 88%

Rare TBK1 variants in patients with frontotemporal dementia and amyotrophic lateral sclerosis in a Chinese cohort

Jiao

Sun

Yuan

et al. 2018

Transl Neurodegener

View full text Add to dashboard Cite

BackgroundThe TANK-Binding Kinase 1 (TBK1) gene has recently been identified as the third or fourth most frequent cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The aim of this study was to assess the genetic contribution of TBK1 in a Chinese cohort.MethodsA total of 270 cases with ALS, FTD, or their combination were recruited into this study. All the coding exons of TBK1 and intron-exon boundaries were sequenced using Sanger sequencing. The frequency of TBK1 variants and the correlation with clinical phenotypes were analyzed.ResultsA novel mutation (c.1959_1960insGT, p.E653fs) was identified in a sporadic case with semantic dementia, secondarily developing ALS. Another novel variant (c.2063_2064delTT, p.L688Rfs*14) was found in an ALS-FTD family. Totally, the TBK1 variants could only account for 0.7% of cases.ConclusionsThis study enlarges the genetic and phenotypic spectrum of TBK1 mutation in a Chinese cohort. Our data indicates that TBK1 mutation is not a common cause for ALS and FTD in Chinese patients.Electronic supplementary materialThe online version of this article (10.1186/s40035-018-0136-6) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionsupporting

confidence: 88%

Rare TBK1 variants in patients with frontotemporal dementia and amyotrophic lateral sclerosis in a Chinese cohort

Jiao

Sun

Yuan

et al. 2018

Transl Neurodegener

View full text Add to dashboard Cite

show abstract

“…In ALS patients, nonsense and frameshift variants in TBK1 act through a haploinsufficiency mechanism. Cellular studies have been performed to better characterize the role of missense variants, demonstrating that missense variants affect phosphorylation of IRF3, a TBK1 target, OPTN binding and phosphorylation, as well as autophosphorylation of TBK1 [ 89 , 143 ]. The mechanism underlying TBK1 pathogenesis can be considered the same for nonsense and missense variants, especially when located in critical domains.…”

Section: Applying the Acmg Standards And Guidelines For The Interpmentioning

confidence: 99%

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Lattante

Marangi

Doronzio

et al. 2020

Genes

View full text Add to dashboard Cite

The development of high-throughput sequencing technologies and screening of big patient cohorts with familial and sporadic amyotrophic lateral sclerosis (ALS) led to the identification of a significant number of genetic variants, which are sometimes difficult to interpret. The American College of Medical Genetics and Genomics (ACMG) provided guidelines to help molecular geneticists and pathologists to interpret variants found in laboratory testing. We assessed the application of the ACMG criteria to ALS-related variants, combining data from literature with our experience. We analyzed a cohort of 498 ALS patients using massive parallel sequencing of ALS-associated genes and identified 280 variants with a minor allele frequency < 1%. Examining all variants using the ACMG criteria, thus considering the type of variant, inheritance, familial segregation, and possible functional studies, we classified 20 variants as “pathogenic”. In conclusion, ALS’s genetic complexity, such as oligogenic inheritance, presence of genes acting as risk factors, and reduced penetrance, needs to be considered when interpreting variants. The goal of this work is to provide helpful suggestions to geneticists and clinicians dealing with ALS.

show abstract

“…Most notably, two recent studies have identified TBK1 as a novel amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causative gene [7,8]. Additional TBK1 mutations characterized by strong penetrance have been disclosed in distinct cohorts of ALS and FTD patients [9][10][11][12].…”

mentioning

confidence: 99%

Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation

Catanese

Heuvel

Mulaw³

et al. 2019

Autophagy

View full text Add to dashboard Cite

Mutations in the TBK1 (TANK binding kinase 1) gene are causally linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TBK1 phosphorylates the cargo receptors OPTN and SQSTM1 regulating a critical step in macroautophagy/autophagy. Disruption of the autophagic flux leads to accumulation of cytosolic protein aggregates, which are a hallmark of ALS. hiPSC-derived TBK1-mutant motoneurons (MNs) showed reduced TBK1 levels and accumulation of cytosolic SQSTM1-positive aggresomes. By screening a library of nuclear-receptor-agonists for modifiers of the SQSTM1 aggregates, we identified 4-hydroxy-(phenyl)retinamide (4HPR) as a potent modifier exerting detrimental effects on mutant-TBK1 motoneurons fitness exacerbating the autophagy overload. We have shown by TEM that TBK1-mutant motoneurons accumulate immature phagophores due a failure in the elongation phase, and 4HPR further worsens the burden of dysfunctional phagophores. 4HPR-increased toxicity was associated with the upregulation of SQSTM1 in a context of strongly reduced ATG10, while rescue of ATG10 levels abolished 4HPR toxicity. Finally, we showed that 4HPR leads to a downregulation of ATG10 and to an accumulation of SQSTM1 + aggresomes also in hiPSC-derived C9orf72-mutant motoneurons. Our data show that cultured human motoneurons harboring mutations in TBK1 gene display typical ALS features, like decreased viability and accumulation of cytosolic SQSTM1-positive aggresomes. The retinoid 4HPR appears a strong negative modifier of the fitness of TBK1 and C9orf72-mutant MNs, through a pathway converging on the mismatch of initiated autophagy and ATG10 levels. Thus, autophagy induction appears not to be a therapeutic strategy for ALS unless the specific underlying pathway alterations are properly addressed.

show abstract

TBK1mutations in Italian patients with amyotrophic lateral sclerosis: genetic and functional characterisation

Cited by 44 publications

References 31 publications

Rare TBK1 variants in patients with frontotemporal dementia and amyotrophic lateral sclerosis in a Chinese cohort

Rare TBK1 variants in patients with frontotemporal dementia and amyotrophic lateral sclerosis in a Chinese cohort

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation

Contact Info

Product

Resources

About