Distal myopathy with coexisting heterozygous TIA1 and MYH7 Variants

Brand, Patricio; Dyck, Peter J.; Liu, Jie; Berini, Sarah E.; Selcen, Duygu; Milone, Margherita

doi:10.1016/j.nmd.2016.05.012

Cited by 14 publications

(9 citation statements)

References 20 publications

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“…Similar to the ALS-related disease proteins TDP-43, hnRNPA1 and FUS, TIA1 is an RNA-binding protein containing a prion-like LCD and assembles into membrane-less organelles, including SGs (Taylor et al, 2016a). A different heterozygous founder mutation that affects the TIA1 LCD (E384K) was previously reported in Swedish/Finnish patients as the cause of Welander distal myopathy (WDM) (Brand et al, 2016; Hackman et al, 2013; Klar et al, 2013), a rimmed vacuolar myopathy characterized by aggregates of TDP-43 and p62. WDM is clinically similar to and shares histopathological features with myopathies caused by mutations in valosin containing protein ( VCP ), p62/SQSTM1 , HNRNPA1 , HNRNPA2B1 and MATR3 , disease genes that have also been associated with ALS/FTD (Fecto et al, 2011; Johnson et al, 2010; Johnson et al, 2014; Kim et al, 2013).…”

Section: Resultsmentioning

confidence: 98%

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics

Mackenzie

Nicholson

Sarkar

et al. 2017

Neuron

517

545

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SUMMARY Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low complexity domain (LCD) of T-cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (P = 8.7×10−6). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.

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Section: Resultsmentioning

confidence: 98%

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics

Mackenzie

Nicholson

Sarkar

et al. 2017

Neuron

517

545

View full text Add to dashboard Cite

show abstract

“…Similar to several other ALS genes, TIA1 encodes a RNA-binding protein comprising a prion-like lowcomplexity sequence domain (LCD). Mutations in this domain were associated with Welander distal myopathy, a pathology also characterized by aggregates of TDP-43 and p62 [77][78][79]. Analysis of 1039 ALS or ALS-FTD patients and 3036 control persons uncovered another six carriers of nonsynonymous variants in the LCD of TIA1, but none in controls, accounting for 2% fALS and <0.5% sALS patients [19].…”

Section: Tia1mentioning

confidence: 99%

ALS Genes in the Genomic Era and their Implications for FTD

2018

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Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease, characterized genetically by a disproportionately large contribution of rare genetic variation. Driven by advances in massive parallel sequencing and applied on large patient-control cohorts, systematic identification of these rare variants that make up the genetic architecture of ALS became feasible. In this review paper, we present a comprehensive overview of recently proposed ALS genes that were identified based on rare genetic variants (TBK1, CHCHD10, TUBA4A, CCNF, MATR3, NEK1, C21orf2, ANXA11, TIA1) and their potential relevance to frontotemporal dementia genetic etiology. As more causal and risk genes are identified, it has become apparent that affected individuals can carry multiple disease-associated variants. In light of this observation, we discuss the oligogenic architecture of ALS. To end, we highlight emerging key molecular processes and opportunities for therapy.

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“…There is also mounting evidence that genes causative of motor neuron disease, hereditary neuropathy or multisystem proteinopathies can result in distal myopathies . In addition, recent studies have demonstrated the digenic nature of certain distal myopathies in which the phenotype results from co‐existing defects in independent genes or from the interplay between different genes and proteins . All this adds complexity to the diagnostic process, the understanding of the pathomechanisms leading to muscle weakness, and the provision of genetic counseling to patients.…”

mentioning

confidence: 99%

The unfolding spectrum of inherited distal myopathies

Milone

Liewluck

2018

Muscle and Nerve

Self Cite

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Distal myopathies are a group of rare muscle diseases characterized by distal weakness at onset. Although acquired myopathies can occasionally present with distal weakness, the majority of distal myopathies have a genetic etiology. Their age of onset varies from early-childhood to late-adulthood while the predominant muscle weakness can affect calf, ankle dorsiflexor, or distal upper limb muscles. A spectrum of muscle pathological changes, varying from nonspecific myopathic changes to rimmed vacuoles to myofibrillar pathology to nuclei centralization, have been noted. Likewise, the underlying molecular defect is heterogeneous. In addition, there is emerging evidence that distal myopathies can result from defective proteins encoded by genes causative of neurogenic disorders, be manifestation of multisystem proteinopathies or the result of the altered interplay between different genes. In this review, we provide an overview on the clinical, electrophysiological, pathological, and molecular aspects of distal myopathies, focusing on the most recent developments in the field. Muscle Nerve, 2018.

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Distal myopathy with coexisting heterozygous TIA1 and MYH7 Variants

Cited by 14 publications

References 20 publications

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics

ALS Genes in the Genomic Era and their Implications for FTD

The unfolding spectrum of inherited distal myopathies

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