{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:18:30Z","timestamp":1790839110925,"version":"4.1.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T00:00:00Z","timestamp":1621382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010892","name":"Department of Science and Technology, Republic of the Philippines","doi-asserted-by":"publisher","award":["FP 15026"],"award-info":[{"award-number":["FP 15026"]}],"id":[{"id":"10.13039\/501100010892","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001350","name":"Ministry of Health -Singapore","doi-asserted-by":"publisher","award":["MOH-TA18may-0003"],"award-info":[{"award-number":["MOH-TA18may-0003"]}],"id":[{"id":"10.13039\/501100001350","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001381","name":"National Research Foundation Singapore","doi-asserted-by":"publisher","award":["NRF-NRFF2016-03"],"award-info":[{"award-number":["NRF-NRFF2016-03"]}],"id":[{"id":"10.13039\/501100001381","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>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 (<jats:italic>MAPT<\/jats:italic>), granulin precursor (<jats:italic>GRN<\/jats:italic>), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin (<jats:italic>OPTN<\/jats:italic>) have rarely been reported. Mutations in <jats:italic>OPTN<\/jats:italic> 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 <jats:italic>OPTN<\/jats:italic> (Chr 10:13166090 G&amp;gt;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 <jats:italic>OPTN<\/jats:italic> 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.<\/jats:p>","DOI":"10.3389\/fneur.2021.645913","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T06:05:08Z","timestamp":1621404308000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Novel Optineurin Frameshift Insertion in a Family With Frontotemporal Dementia and Parkinsonism Without Amyotrophic Lateral Sclerosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Jacqueline","family":"Dominguez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeryl Tan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Jayne","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlene","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma Fe","family":"De Guzman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boots","family":"Natividad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma Luisa","family":"Daroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jemellee","family":"Cano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Lian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weng Khong","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia Nee","family":"Foo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeline S. L.","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1212\/01.wnl.0000187068.92184.63","article-title":"Comparison of family histories in FTLD subtypes and related tauopathies","volume":"65","author":"Goldman","year":"2005","journal-title":"Neurology."},{"key":"B2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1111\/jnc.13654","article-title":"The clinical spectrum of sporadic and familial forms of frontotemporal dementia","volume":"138","author":"Woollacott","year":"2016","journal-title":"J Neurochem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2456","DOI":"10.1093\/brain\/awr179","article-title":"Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia","volume":"134","author":"Rascovsky","year":"2011","journal-title":"Brain."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1212\/WNL.0b013e31821103e6","article-title":"Classification of primary progressive aphasia and its variants","volume":"76","author":"Gorno-Tempini","year":"2011","journal-title":"Neurology."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2075","DOI":"10.1007\/s00415-019-09363-4","article-title":"An update on genetic frontotemporal dementia","volume":"266","author":"Greaves","year":"2019","journal-title":"J Neurol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-Linked FTD and ALS","volume":"72","author":"DeJesus-Hernandez","year":"2011","journal-title":"Neuron."},{"key":"B7","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/S1474-4422(12)70046-7","article-title":"C9orf72 repeat expansions in patients with ALS and FTD","volume":"11","author":"Rademakers","year":"2012","journal-title":"Lancet Neurol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1002\/ana.21612","article-title":"TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration","volume":"65","author":"Benajiba","year":"2009","journal-title":"Ann Neurol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1556","DOI":"10.1212\/WNL.0b013e31826e25df","article-title":"SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"79","author":"Rubino","year":"2012","journal-title":"Neurology."},{"key":"B10","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1515\/REVNEURO.2010.21.4.251","article-title":"Pathogenic TARDBP mutations in amyotrophic lateral sclerosis and frontotemporal dementia: disease-associated pathways","volume":"21","author":"Barmada","year":"2010","journal-title":"Rev Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s00401-015-1436-x","article-title":"Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease","volume":"130","author":"Pottier","year":"2015","journal-title":"Acta Neuropathol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1136\/jnnp.2011.242313","article-title":"Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis","volume":"82","author":"Del Bo","year":"2011","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"B13","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/nature08971","article-title":"Mutations of optineurin in amyotrophic lateral sclerosis","volume":"465","author":"Maruyama","year":"2010","journal-title":"Nature."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1002\/acn3.50928","article-title":"Novel mutation in optineurin causing aggressive ALS+\/\u2013frontotemporal dementia","volume":"6","author":"Feng","year":"2019","journal-title":"Ann Clin Transl Neurol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1080\/21678421.2018.1452947","article-title":"Identification of compound heterozygous variants in OPTN in an ALS-FTD patient from the CReATe consortium: a case report","volume":"19","author":"Pottier","year":"2018","journal-title":"Amyotroph Lateral Scler Front Degener."},{"key":"B16","doi-asserted-by":"publisher","first-page":"194.e1","DOI":"10.1016\/j.neurobiolaging.2017.01.004","article-title":"Comprehensive targeted next-generation sequencing in Japanese familial amyotrophic lateral sclerosis","volume":"53","author":"Nishiyama","year":"2017","journal-title":"Neurobiol Aging."},{"key":"B17","doi-asserted-by":"publisher","first-page":"148.e9","DOI":"10.1016\/j.neurobiolaging.2020.07.014","article-title":"Underlying genetic variation in familial frontotemporal dementia: sequencing of 198 patients","volume":"97","author":"Mol","year":"2021","journal-title":"Neurobiol Aging."},{"key":"B18","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1001\/archpsyc.1983.01790060110016","article-title":"The mini-mental state examination","volume":"40","author":"Folstein","year":"1983","journal-title":"Arch Gen Psychiatry."},{"key":"B19","doi-asserted-by":"publisher","first-page":"160","DOI":"10.4236\/aad.2014.34015","article-title":"Early detection of mild alzheimer's disease in filipino elderly: validation of the montreal cognitive assessment-philippines (MoCA-P)","volume":"3","author":"Dominguez","year":"2014","journal-title":"Adv Alzheimer Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1002\/mds.10473","article-title":"The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations","volume":"18","year":"2003","journal-title":"Mov Disord."},{"key":"B21","doi-asserted-by":"publisher","first-page":"160.e15","DOI":"10.1016\/j.neurobiolaging.2018.04.003","article-title":"Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement","volume":"68","author":"Ng","year":"2018","journal-title":"Neurobiol Aging."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with burrows-wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics."},{"key":"B23","unstructured":"LiH\n          Aligning Sequence Reads, Clone Sequences and Assembly Contigs With BWA-MEM2013"},{"key":"B24","doi-asserted-by":"crossref","unstructured":"AuweraGA\n            CarneiroMO\n            HartlC\n          From Fast Data to High-Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline2013","DOI":"10.1002\/0471250953.bi1110s43"},{"key":"B25","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1556","DOI":"10.1038\/nprot.2015.105","article-title":"Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR","volume":"10","author":"Yang","year":"2015","journal-title":"Nat Protoc."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nprot.2015.123","article-title":"SIFT missense predictions for genomes","volume":"11","author":"Vaser","year":"2016","journal-title":"Nat Protoc."},{"key":"B28","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1002\/0471142905.hg0720s76","article-title":"Predicting functional effect of human missense mutations using polyphen-2","volume":"76","author":"Adzhubei","year":"2013","journal-title":"Curr Protoc Hum Genet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B30","unstructured":"2020"},{"key":"B31","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.it.2016.07.002","article-title":"Cellular functions of optineurin in health and disease","volume":"37","author":"Slowicka","year":"2016","journal-title":"Trends Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pneurobio.2017.04.005","article-title":"Optineurin in amyotrophic lateral sclerosis: multifunctional adaptor protein at the crossroads of different neuroprotective mechanisms","volume":"154","author":"Markovinovic","year":"2017","journal-title":"Prog Neurobiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1212\/WNL.0000000000002334","article-title":"OPTN 691_692insAG is a founder mutation causing recessive ALS and increased risk in heterozygotes","volume":"86","author":"Goldstein","year":"2016","journal-title":"Neurology."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1764.e9","DOI":"10.1016\/j.neurobiolaging.2014.12.032","article-title":"The distinct genetic pattern of ALS in Turkey and novel mutations","volume":"36","author":"\u00d6zoguz","year":"2015","journal-title":"Neurobiol Aging."},{"key":"B35","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1136\/jnnp-2017-317611","article-title":"Comprehensive analysis of the mutation spectrum in 301 German ALS families","volume":"89","author":"M\u00fcller","year":"2018","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.7490\/f1000research.1113439.1","article-title":"A novel optineurin truncation mutation identified in a consanguineous palestinian family with amyotrophic lateral sclerosis confirms loss of function as a disease mechanism","author":"Gotkine","year":"2016","journal-title":"E Pub"},{"key":"B37","doi-asserted-by":"publisher","first-page":"3830","DOI":"10.1093\/hmg\/ddv126","article-title":"Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis","volume":"24","author":"Sundaramoorthy","year":"2015","journal-title":"Hum Mol Genet."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1126\/science.aaa3650","article-title":"Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways","volume":"347","author":"Cirulli","year":"2015","journal-title":"Science (80-)"},{"key":"B39","doi-asserted-by":"publisher","first-page":"208.e1","DOI":"10.1016\/j.neurobiolaging.2011.07.001","article-title":"A novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS","volume":"33","author":"T\u00fcmer","year":"2012","journal-title":"Neurobiol Aging."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1212\/01.wnl.0000319702.37497.72","article-title":"Distinct genetic forms of frontotemporal dementia","volume":"71","author":"Seelaar","year":"2008","journal-title":"Neurology."},{"key":"B41","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1093\/brain\/awm331","article-title":"Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations","volume":"131","author":"Pickering-Brown","year":"2008","journal-title":"Brain."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1212\/WNL.0b013e3181bf997a","article-title":"The heritability and genetics of frontotemporal lobar degeneration","volume":"73","author":"Rohrer","year":"2009","journal-title":"Neurology."},{"key":"B43","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1007\/s12031-011-9632-1","article-title":"Parkinsonism and frontotemporal dementia: the clinical overlap","volume":"45","author":"Espay","year":"2011","journal-title":"J Mol Neurosci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1514","DOI":"10.3390\/ijms20061514","article-title":"Analysis of 50 neurodegenerative genes in clinically diagnosed early-onset Alzheimer's disease","volume":"20","author":"Giau","year":"2019","journal-title":"Int J Mol Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1016\/j.parkreldis.2014.06.004","article-title":"Parkinsonian syndrome in familial frontotemporal dementia","volume":"20","author":"Siuda","year":"2014","journal-title":"Parkinsonism Relat Disord."},{"key":"B46","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/nrneurol.2016.14","article-title":"Parkinsonism, movement disorders and genetics in frontotemporal dementia","volume":"12","author":"Baizabal-Carvallo","year":"2016","journal-title":"Nat Rev Neurol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"e0153852","DOI":"10.1371\/journal.pone.0153852","article-title":"Characterization of movement disorder phenomenology in genetically proven, familial frontotemporal lobar degeneration: a systematic review and meta-Analysis","volume":"11","author":"Gasca-Salas","year":"2016","journal-title":"PLoS ONE."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.645913\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T06:05:13Z","timestamp":1621404313000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.645913\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,19]]},"references-count":47,"alternative-id":["10.3389\/fneur.2021.645913"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2021.645913","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,19]]},"article-number":"645913"}}