TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics
Ian R. MackenzieAlexandra M. NicholsonMohona SarkarJames MessingMaria D. PuriceCyril PottierKavya AnnuMatt BakerRalph B. PerkersonAishe KurtiBillie J. MatchettTanja MittagJamshid TemirovGing‐Yuek Robin HsiungCharles KriegerMelissa E. MurrayMasato KatoJohn Denis FryerLeonard PetrucelliLorne ZinmanSandra WeıntraubMarsel MesulamJulia KeithSasha ŽivkovićVeronica Hirsch‐ReinshagenRaymond P. RoosStephan ZüchnerNeill R. Graff‐RadfordRonald C. PetersenRichard J. CaselliZbigniew K. WszołekElizabeth FingerCarol F. LippaDavid LacomisHeather StewartDennis W. DicksonHong Joo KimEkaterina RogaevaEileen H. BigioKhrista BoylanJ. Paul TaylorRosa Rademakers
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Stress granule
C9ORF72
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Objective
To further assess the presence of a large hexanucleotide repeat expansion in the first intron of the C9orf72 gene identified as the genetic cause of chromosome 9p21–linked amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) in 4 unrelated families with a conclusive linkage to c9ALS/FTD.Design
A repeat-primed polymerase chain reaction assay.Setting
Academic research.Participants
Affected and unaffected individuals from 4 ALS/FTD families.Main Outcome Measure
The amplified C9orf72 repeat expansion.Results
We show that the repeat is expanded in and segregated perfectly with the disease in these 4 pedigrees.Conclusion
Our findings further confirm the C9orf72 hexanucleotide repeat expansion as the causative mutation for c9ALS/FTD and strengthen the hypothesis that ALS and FTD belong to the same disease spectrum.C9ORF72
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Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have a strong clinical, genetic and pathological overlap. This review focuses on the current understanding of structural, functional and molecular neuroimaging signatures of genetic FTD and ALS. We overview quantitative neuroimaging studies on the most common genes associated with FTD (MAPT, GRN), ALS (SOD1), and both (C9orf72), and summarize visual observations of images reported in the rarer genes (CHMP2B, TARDBP, FUS, OPTN, VCP, UBQLN2, SQSTM1, TREM2, CHCHD10, TBK1).
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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) were independently described in clinical and pathological details more than a century ago. Recent breakthrough discoveries identifying common genes that are causal to either ALS or FTD or an overlapping ALS-FTD syndrome have dramatically transformed our view regarding their pathogenesis. Most recently, a massive hexanucleotide (GGGGCC) repeat expansion mutation in C9orf72 gene has been linked to the majority of familial ALS, FTD and mixed ALS-FTD cases. C9orf72 and other genes causal to ALS and FTD are consistently associated with the formation of cellular RNA inclusions and protein aggregates. This article summarizes the recently reported ALS-FTD-linked genes and the emerging common unifying mechanism in the pathogenesis of ALS-FTD spectrum disorders along with a comment on the potential new therapeutic targets in these hitherto incurable diseases.
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The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.
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There is a close association between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on a clinical, pathological and genetic level. Three causative genes are responsible for over 80% of cases of FTD in families with a clear autosomal dominant family history: MAPT, GRN, and C9ORF72. Rarer genetic causes of FTD include mutations in the VCP, FUS, and CHMP2B genes. In this chapter, we discuss the genetic background of FTD-ALS overlap syndromes with a focus on when to suspect a mutation in the C9ORF72 is responsible. It has been recently established that an expanded hexanucleotide repeat in this gene is the most common cause of familial FTD and ALS.The presence of psychiatric symptoms in the context of FTD-ALS should alert clinicians to the possibility of a C9ORF72 expansion.
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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. Objectives The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 ( C9orf72 ) hexanucleotide repeat expansion, the most important genetic cause in both diseases. Methods From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72 . Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes. Results We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1 , with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15 , VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4 . Conclusion Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15 , FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease.
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