Identification of compound heterozygous variants in <i>OPTN</i> in an ALS-FTD patient from the CReATe consortium: a case report

Pottier, Cyril; Rampersaud, Evadnie; Baker, Matt; Wu, Gang; Wuu, Joanne; McCauley, Jacob L.; Züchner, Stephan; Schüle, Rebecca; Bermudez, C; Hussain, Sumaira; Cooley, Anne; Wallace, Marielle; Zhang, Jinghui; Taylor, J. Paul; Benatar, Michael; Rademakers, Rosa

doi:10.1080/21678421.2018.1452947

Cited by 17 publications

(11 citation statements)

References 10 publications

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“…C9orf72 [139], SOD1 [140], FUS [141,142], TARDBP [143,144], CHCHD10 [145,146], UBQLN2 [147], SQSTM1 [148,149], OPTN [150,151], VCP [152,153], TBK1 [154], MAPT [155], GRN [156], CYLD [157] Impairment of Nup35, Nup50, Nup54, Nup58, Nup62, Nup88, Nup93, Nup98, Nup107, Nup153, Nup155, Nup160, Nup188, Nup205, Nup214, Nup358, Kapβ1, RanGAP1, importin-α/β, Xpo5, Gle1, Nxf1 [158][159][160][161][162][163][164].…”

Section: Als/ftdmentioning

confidence: 99%

Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration

Ding

Sepehrimanesh

2021

IJMS

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Nucleocytoplasmic transport (NCT) across the nuclear envelope is precisely regulated in eukaryotic cells, and it plays critical roles in maintenance of cellular homeostasis. Accumulating evidence has demonstrated that dysregulations of NCT are implicated in aging and age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and Huntington disease (HD). This is an emerging research field. The molecular mechanisms underlying impaired NCT and the pathogenesis leading to neurodegeneration are not clear. In this review, we comprehensively described the components of NCT machinery, including nuclear envelope (NE), nuclear pore complex (NPC), importins and exportins, RanGTPase and its regulators, and the regulatory mechanisms of nuclear transport of both protein and transcript cargos. Additionally, we discussed the possible molecular mechanisms of impaired NCT underlying aging and neurodegenerative diseases, such as ALS/FTD, HD, and AD.

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Section: Als/ftdmentioning

confidence: 99%

Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration

Ding

Sepehrimanesh

2021

IJMS

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“…TBK1 mutations were first linked to ALS (Cirulli et al, 2015;Freischmidt et al, 2015), FTD (Gijselinck et al, 2015;Le Ber et al, 2015) and ALS-FTD in 2015 (Pottier et al, 2015). Loss of function (LoF) mutations, including frameshifts, splice-site alterations, read-throughs and nonsense mutations have been reported to show definite or probable pathogenicity.…”

Section: Ftdals4: Tank-binding Kinase (Tbk1)mentioning

confidence: 99%

“…TBK1 codes the TBK1 (TANK-binding kinase 1) protein, a kinase which binds and phosphorylates proteins involved in innate immunity (Pilli et al, 2012), autophagy (Korac et al, 2013), and mitophagy (Heo et al, 2015). Protein targets include optineurin (OPTN) (ALS12) and p62 (SQSTM1) (FTDALS3), two ALS-FTD associated genes (Maruyama et al, 2010;Rea et al, 2014) and mutations in both of these genes have been found along with TBK1 mutations in patients (Pottier et al, 2015;Borghero et al, 2016;Dols-Icardo et al, 2018;Lattante et al, 2019).…”

Section: Ftdals4: Tank-binding Kinase (Tbk1)mentioning

confidence: 99%

“…Subsequently, more than 20 mutations have been described although not all have been investigated in in vitro and in vivo disease models. The incidence of OPTN mutations in FTD is still under debate, as one study reported copy number variants in OPTN in 4.8% of FTD cases (Pottier et al, 2015) while another study, recruiting a larger cohort of 371 FTD cases, did not detect any mutations using whole exome sequencing (Rollinson et al, 2012). More recently, a patient with ALS-FTD was reported with compound heterozygous mutations, resulting in a 75-80% reduction in OPTN (Pottier et al, 2018).…”

Section: Als12: Optineurin (Optn)mentioning

confidence: 99%

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Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

et al. 2020

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“…OPTN mutations were first linked to ALS in the Japanese population, accounting for 3.3% of familial ALS (FALS) and 0.2% of sporadic ALS (sALS) patients ( 13 ). Rare reports of OPTN mutations linked to FTD or displaying an FTD phenotype include a Chinese patient heterozygous for a OPTN c.1546G> C (p.E516Q) mutation with a rapidly progressive ALS-FTD phenotype ( 14 ), and two male patients with onset in the 5th decade of ALS-FTD, carrying novel compound heterozygous loss-of-function mutations in OPTN (nonsense variant p.Ser262* and frameshift deletion p.Leu430Argfs*16) ( 15 ), and heterozygous for the OPTN p.E478G variant ( 16 ), respectively. A novel homozygous splice-site variant (c.1242þ1G>A) was recently reported in a patient with logopenic variant FTD (lvFTD) and whose sibling was diagnosed with non-fluent variant FTD.…”

Section: Introductionmentioning

confidence: 99%

Novel Optineurin Frameshift Insertion in a Family With Frontotemporal Dementia and Parkinsonism Without Amyotrophic Lateral Sclerosis

Dominguez

Tan

et al. 2021

Front. Neurol.

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Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene (MAPT), granulin precursor (GRN), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin (OPTN) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with four members harboring a novel frameshift insertion at OPTN (Chr 10:13166090 G>GA) p.Lys328GluTer11, three of whom presented with FTD-related phenotypes. Additionally, one sibling heterozygous for the frameshift insertion had a predominantly parkinsonian phenotype resembling corticobasal syndrome, but it remains to be determined if this phenotype is related to the frameshift insertion. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity.

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Identification of compound heterozygous variants in OPTN in an ALS-FTD patient from the CReATe consortium: a case report

Cited by 17 publications

References 10 publications

Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration

Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration

Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

Novel Optineurin Frameshift Insertion in a Family With Frontotemporal Dementia and Parkinsonism Without Amyotrophic Lateral Sclerosis

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