{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T09:28:49Z","timestamp":1789118929622,"version":"build-2803163510"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Psychiatry"],"published-print":{"date-parts":[[2026,10]]},"DOI":"10.1038\/s41380-026-03653-w","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T17:52:45Z","timestamp":1779126765000},"page":"5719-5726","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protective TMEM106B-rs3173615 delays age at onset in GRN mutation carriers"],"prefix":"10.1038","volume":"31","author":[{"given":"Lorenzo","family":"Pagano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8618-4282","authenticated-orcid":false,"given":"Claudia","family":"Saraceno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Geviti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Fostinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Facconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Lagan\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Giacomucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Sofia","family":"Cotelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Assunta","family":"Ingannato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Bagnoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8292-6434","authenticated-orcid":false,"given":"Antonio","family":"Longobardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6279-5983","authenticated-orcid":false,"given":"Alice","family":"Russotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Bellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Lagrotteria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ersilia","family":"Paparazzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliano","family":"Binetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Montesanto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9338-9040","authenticated-orcid":false,"given":"Benedetta","family":"Nacmias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Maletta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Borroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7691-1957","authenticated-orcid":false,"given":"Roberta","family":"Ghidoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"3653_CR1","doi-asserted-by":"publisher","first-page":"1672","DOI":"10.1016\/S0140-6736(15)00461-4","volume":"386","author":"J Bang","year":"2015","unstructured":"Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015;386:1672\u201382.","journal-title":"Lancet"},{"key":"3653_CR2","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.1212\/WNL.58.11.1615","volume":"58","author":"E Ratnavalli","year":"2002","unstructured":"Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology. 2002;58:1615\u201321.","journal-title":"Neurology"},{"key":"3653_CR3","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1212\/WNL.0b013e3181bf997a","volume":"73","author":"JD Rohrer","year":"2009","unstructured":"Rohrer JD, Guerreiro R, Vandrovcova J, Uphill J, Reiman D, Beck J, et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology. 2009;73:1451\u20136.","journal-title":"Neurology"},{"key":"3653_CR4","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1001\/jamaneurol.2013.3956","volume":"70","author":"EM Wood","year":"2013","unstructured":"Wood EM, Falcone D, Suh E, Irwin DJ, Chen-Plotkin AS, Lee EB, et al. Development and validation of pedigree classification criteria for frontotemporal lobar degeneration. JAMA Neurol. 2013;70:1411\u20137.","journal-title":"JAMA Neurol"},{"key":"3653_CR5","doi-asserted-by":"publisher","first-page":"753","DOI":"10.3233\/JAD-170661","volume":"61","author":"S Fostinelli","year":"2018","unstructured":"Fostinelli S, Ciani M, Zanardini R, Zanetti O, Binetti G, Ghidoni R, et al. The heritability of frontotemporal lobar degeneration: validation of pedigree classification criteria in a northern Italy cohort. J Alzheimers Dis. 2018;61:753\u201360.","journal-title":"J Alzheimers Dis"},{"key":"3653_CR6","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1038\/nature05016","volume":"442","author":"M Baker","year":"2006","unstructured":"Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442:916\u20139.","journal-title":"Nature"},{"key":"3653_CR7","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1038\/nature05017","volume":"442","author":"M Cruts","year":"2006","unstructured":"Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006;442:920\u20134.","journal-title":"Nature"},{"key":"3653_CR8","doi-asserted-by":"publisher","first-page":"2988","DOI":"10.1093\/hmg\/ddl241","volume":"15","author":"J Gass","year":"2006","unstructured":"Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, et al. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet. 2006;15:2988\u20133001.","journal-title":"Hum Mol Genet"},{"key":"3653_CR9","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1097\/WAD.0b013e3181d1bb13","volume":"24","author":"L Benussi","year":"2010","unstructured":"Benussi L, Ghidoni R, Binetti G. Progranulin mutations are a common cause of FTLD in Northern Italy. Alzheimer Dis Assoc Disord. 2010;24:308\u20139.","journal-title":"Alzheimer Dis Assoc Disord"},{"key":"3653_CR10","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1002\/bies.200900086","volume":"31","author":"A Bateman","year":"2009","unstructured":"Bateman A, Bennett HPJ. The granulin gene family: from cancer to dementia. Bioessays. 2009;31:1245\u201354.","journal-title":"Bioessays"},{"key":"3653_CR11","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1212\/01.wnl.0000325058.10218.fc","volume":"71","author":"R Ghidoni","year":"2008","unstructured":"Ghidoni R, Benussi L, Glionna M, Franzoni M, Binetti G. Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration. Neurology. 2008;71:1235\u20139.","journal-title":"Neurology"},{"key":"3653_CR12","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1001\/archneur.64.8.1148","volume":"64","author":"VM Van Deerlin","year":"2007","unstructured":"Van Deerlin VM, Wood EM, Moore P, Yuan W, Forman MS, Clark CM, et al. Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations. Arch Neurol. 2007;64:1148\u201353.","journal-title":"Arch Neurol"},{"key":"3653_CR13","doi-asserted-by":"publisher","first-page":"171","DOI":"10.3389\/fnagi.2015.00171","volume":"7","author":"A Benussi","year":"2015","unstructured":"Benussi A, Padovani A, Borroni B. Phenotypic heterogeneity of monogenic frontotemporal dementia. Front Aging Neurosci. 2015;7:171.","journal-title":"Front Aging Neurosci"},{"key":"3653_CR14","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1212\/01.wnl.0000319702.37497.72","volume":"71","author":"H Seelaar","year":"2008","unstructured":"Seelaar H, Kamphorst W, Rosso SM, Azmani A, Masdjedi R, de Koning I, et al. Distinct genetic forms of frontotemporal dementia. Neurology. 2008;71:1220\u20136.","journal-title":"Neurology"},{"key":"3653_CR15","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1016\/S1474-4422(08)70194-7","volume":"7","author":"JC van Swieten","year":"2008","unstructured":"van Swieten JC, Heutink P. Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia. Lancet Neurol. 2008;7:965\u201374.","journal-title":"Lancet Neurol"},{"key":"3653_CR16","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/S1474-4422(19)30394-1","volume":"19","author":"KM Moore","year":"2020","unstructured":"Moore KM, Nicholas J, Grossman M, McMillan CT, Irwin DJ, Massimo L, et al. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 2020;19:145\u201356.","journal-title":"Lancet Neurol"},{"key":"3653_CR17","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/S1474-4422(07)70221-1","volume":"6","author":"R Rademakers","year":"2007","unstructured":"Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, et al. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C->T (Arg493X) mutation: an international initiative. Lancet Neurol. 2007;6:857\u201368.","journal-title":"Lancet Neurol"},{"key":"3653_CR18","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.tins.2009.05.005","volume":"32","author":"R Rademakers","year":"2009","unstructured":"Rademakers R, Rovelet-Lecrux A. Recent insights into the molecular genetics of dementia. Trends Neurosci. 2009;32:451\u201361.","journal-title":"Trends Neurosci"},{"key":"3653_CR19","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1038\/ng.536","volume":"42","author":"VM Van Deerlin","year":"2010","unstructured":"Van Deerlin VM, Sleiman PMA, Martinez-Lage M, Chen-Plotkin A, Wang L, Graff-Radford NR, et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet. 2010;42:234\u20139.","journal-title":"Nat Genet"},{"key":"3653_CR20","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1001\/archneurol.2010.350","volume":"68","author":"C Cruchaga","year":"2011","unstructured":"Cruchaga C, Graff C, Chiang H, Wang J, Hinrichs AL, Spiegel N, et al. Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch Neurol. 2011;68:581\u20136.","journal-title":"Arch Neurol"},{"key":"3653_CR21","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1212\/WNL.0b013e31820a0e3b","volume":"76","author":"N Finch","year":"2011","unstructured":"Finch N, Carrasquillo MM, Baker M, Rutherford NJ, Coppola G, Dejesus-Hernandez M, et al. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology. 2011;76:467\u201374.","journal-title":"Neurology"},{"key":"3653_CR22","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1093\/brain\/awr007","volume":"134","author":"J van der Zee","year":"2011","unstructured":"van der Zee J, Van Langenhove T, Kleinberger G, Sleegers K, Engelborghs S, Vandenberghe R, et al. TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. Brain. 2011;134:808\u201315.","journal-title":"Brain"},{"key":"3653_CR23","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1111\/jnc.12329","volume":"126","author":"AM Nicholson","year":"2013","unstructured":"Nicholson AM, Finch NA, Wojtas A, Baker MC, Perkerson RB, Castanedes-Casey M, et al. TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia. J Neurochem. 2013;126:781\u201391.","journal-title":"J Neurochem"},{"key":"3653_CR24","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1016\/S1474-4422(18)30126-1","volume":"17","author":"C Pottier","year":"2018","unstructured":"Pottier C, Zhou X, Perkerson RB, Baker M, Jenkins GD, Serie DJ, et al. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol. 2018;17:548\u201358.","journal-title":"Lancet Neurol"},{"key":"3653_CR25","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adf9735","volume":"16","author":"JD Marks","year":"2024","unstructured":"Marks JD, Ayuso VE, Carlomagno Y, Yue M, Todd TW, Hao Y, et al. TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia. Sci Transl Med. 2024;16:eadf9735.","journal-title":"Sci Transl Med"},{"key":"3653_CR26","doi-asserted-by":"publisher","first-page":"7035","DOI":"10.3390\/ijms25137035","volume":"25","author":"C Saraceno","year":"2024","unstructured":"Saraceno C, Pagano L, Lagan\u00e0 V, Geviti A, Bagnoli S, Ingannato A, et al. Mutational landscape of alzheimer\u2019s disease and frontotemporal dementia: regional variances in northern, central, and southern Italy. Int J Mol Sci. 2024;25:7035.","journal-title":"Int J Mol Sci"},{"key":"3653_CR27","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17:405\u201324.","journal-title":"Genet Med"},{"key":"3653_CR28","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","volume":"35","author":"C Kopanos","year":"2019","unstructured":"Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35:1978\u201380.","journal-title":"Bioinformatics"},{"key":"3653_CR29","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1007\/s00439-020-02199-3","volume":"139","author":"PD Stenson","year":"2020","unstructured":"Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, et al. The human gene mutation database (HGMD\u00ae): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197\u2013207.","journal-title":"Hum Genet"},{"key":"3653_CR30","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s13195-024-01420-z","volume":"16","author":"IJ Swift","year":"2024","unstructured":"Swift IJ, Rademakers R, Finch N, Baker M, Ghidoni R, Benussi L, et al. A systematic review of progranulin concentrations in biofluids in over 7000 people-assessing the pathogenicity of GRN mutations and other influencing factors. Alzheimers Res Ther. 2024;16:66.","journal-title":"Alzheimers Res Ther"},{"key":"3653_CR31","doi-asserted-by":"publisher","first-page":"2456","DOI":"10.1093\/brain\/awr179","volume":"134","author":"K Rascovsky","year":"2011","unstructured":"Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134:2456\u201377.","journal-title":"Brain"},{"key":"3653_CR32","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1212\/WNL.0b013e31821103e6","volume":"76","author":"ML Gorno-Tempini","year":"2011","unstructured":"Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76:1006\u201314.","journal-title":"Neurology"},{"key":"3653_CR33","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","volume":"30","author":"AM Bolger","year":"2014","unstructured":"Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114\u201320.","journal-title":"Bioinformatics"},{"key":"3653_CR34","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","volume":"26","author":"H Li","year":"2010","unstructured":"Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26:589\u201395.","journal-title":"Bioinformatics"},{"key":"3653_CR35","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","volume":"38","author":"K Wang","year":"2010","unstructured":"Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.","journal-title":"Nucleic Acids Res"},{"key":"3653_CR36","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1093\/nar\/gkt1113","volume":"42","author":"MJ Landrum","year":"2014","unstructured":"Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42:980.","journal-title":"Nucleic Acids Res"},{"key":"3653_CR37","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/ng.2892","volume":"46","author":"M Kircher","year":"2014","unstructured":"Kircher M, Witten DM, Jain P, O\u2019Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310\u20135.","journal-title":"Nat Genet"},{"key":"3653_CR38","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"IA Adzhubei","year":"2010","unstructured":"Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248\u20139.","journal-title":"Nat Methods"},{"key":"3653_CR39","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1093\/nar\/gkg509","volume":"31","author":"PC Ng","year":"2003","unstructured":"Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812\u20134.","journal-title":"Nucleic Acids Res"},{"key":"3653_CR40","doi-asserted-by":"publisher","first-page":"e46688","DOI":"10.1371\/journal.pone.0046688","volume":"7","author":"Y Choi","year":"2012","unstructured":"Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the functional effect of amino acid substitutions and indels. PLoS One. 2012;7:e46688.","journal-title":"PLoS One"},{"key":"3653_CR41","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1002\/humu.22225","volume":"34","author":"HA Shihab","year":"2013","unstructured":"Shihab HA, Gough J, Cooper DN, Stenson PD, Barker GLA, Edwards KJ, et al. Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models. Hum Mutat. 2013;34:57\u201365.","journal-title":"Hum Mutat"},{"key":"3653_CR42","doi-asserted-by":"publisher","first-page":"e1001025","DOI":"10.1371\/journal.pcbi.1001025","volume":"6","author":"EV Davydov","year":"2010","unstructured":"Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol. 2010;6:e1001025.","journal-title":"PLoS Comput Biol"},{"key":"3653_CR43","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alf\u00f6ldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434\u201343.","journal-title":"Nature"},{"key":"3653_CR44","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1093\/nar\/gki375","volume":"33","author":"E Capriotti","year":"2005","unstructured":"Capriotti E, Fariselli P, Casadio R. I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res. 2005;33:306.","journal-title":"Nucleic Acids Res"},{"key":"3653_CR45","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1002\/prot.20810","volume":"62","author":"J Cheng","year":"2006","unstructured":"Cheng J, Randall A, Baldi P. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins. 2006;62:1125\u201332.","journal-title":"Proteins"},{"key":"3653_CR46","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1007\/s00439-020-02246-z","volume":"140","author":"T Khanna","year":"2021","unstructured":"Khanna T, Hanna G, Sternberg MJE, David A. Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants. Hum Genet. 2021;140:805\u201312.","journal-title":"Hum Genet"},{"key":"3653_CR47","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1111\/j.2517-6161.1972.tb00899.x","volume":"34","author":"DR Cox","year":"1972","unstructured":"Cox DR. Regression models and life-tables. J R Stat Soc Ser B (Methodological). 1972;34:187\u2013202.","journal-title":"J R Stat Soc Ser B (Methodological)"},{"key":"3653_CR48","doi-asserted-by":"publisher","first-page":"221.e1","DOI":"10.1016\/j.neurobiolaging.2017.06.026","volume":"59","author":"N Rostgaard","year":"2017","unstructured":"Rostgaard N, Roos P, Budtz-J\u00f8rgensen E, Johannsen P, Waldemar G, N\u00f8rrem\u00f8lle A, et al. TMEM106B and ApoE polymorphisms in CHMP2B-mediated frontotemporal dementia (FTD-3). Neurobiol Aging. 2017;59:221.e1\u2013221.e7.","journal-title":"Neurobiol Aging"},{"key":"3653_CR49","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1111\/j.0006-341X.2000.01016.x","volume":"56","author":"S Ripatti","year":"2000","unstructured":"Ripatti S, Palmgren J. Estimation of multivariate frailty models using penalized partial likelihood. Biometrics. 2000;56:1016\u201322.","journal-title":"Biometrics"},{"key":"3653_CR50","doi-asserted-by":"publisher","first-page":"1784","DOI":"10.1093\/brain\/awx103","volume":"140","author":"E Premi","year":"2017","unstructured":"Premi E, Grassi M, van Swieten J, Galimberti D, Graff C, Masellis M, et al. Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study. Brain. 2017;140:1784\u201391.","journal-title":"Brain"},{"key":"3653_CR51","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000209832","volume":"103","author":"M Vandebergh","year":"2024","unstructured":"Vandebergh M, Ramos EM, Corriveau-Lecavalier N, Ramanan VK, Kornak J, Mester C, et al. Gene-specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration. Neurology. 2024;103:e209832.","journal-title":"Neurology"},{"key":"3653_CR52","doi-asserted-by":"publisher","first-page":"2746","DOI":"10.1093\/brain\/awaf019","volume":"148","author":"SS Mirza","year":"2025","unstructured":"Mirza SS, Pasternak M, Paterson AD, Rogaeva E, Tartaglia MC, Mitchell SB, et al. Disease-modifying effects of TMEM106B in genetic frontotemporal dementia: a longitudinal GENFI study. Brain. 2025;148:2746\u201362.","journal-title":"Brain"},{"key":"3653_CR53","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1007\/s00415-024-12758-7","volume":"272","author":"JFH De Houwer","year":"2024","unstructured":"De Houwer JFH, Dopper EGP, Rajicic A, van Buuren R, Arcaro M, Galimberti D, et al. Two novel variants in GRN: the relevance of CNV analysis and genetic screening in FTLD patients with a negative family history. J Neurol. 2024;272:64.","journal-title":"J Neurol"},{"key":"3653_CR54","doi-asserted-by":"publisher","first-page":"19670","DOI":"10.1074\/jbc.M113.515700","volume":"289","author":"OA Brady","year":"2014","unstructured":"Brady OA, Zhou X, Hu F. Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a). J Biol Chem. 2014;289:19670\u201380.","journal-title":"J Biol Chem"},{"key":"3653_CR55","doi-asserted-by":"publisher","first-page":"11213","DOI":"10.1523\/JNEUROSCI.0521-12.2012","volume":"32","author":"AS Chen-Plotkin","year":"2012","unstructured":"Chen-Plotkin AS, Unger TL, Gallagher MD, Bill E, Kwong LK, Volpicelli-Daley L, et al. TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132\/212 cluster and affects progranulin pathways. J Neurosci. 2012;32:11213\u201327.","journal-title":"J Neurosci"},{"key":"3653_CR56","doi-asserted-by":"publisher","first-page":"19355","DOI":"10.1074\/jbc.M112.365098","volume":"287","author":"CM Lang","year":"2012","unstructured":"Lang CM, Fellerer K, Schwenk BM, Kuhn P, Kremmer E, Edbauer D, et al. Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. J Biol Chem. 2012;287:19355\u201365.","journal-title":"J Biol Chem"},{"key":"3653_CR57","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/2051-5960-1-36","volume":"1","author":"JI Busch","year":"2013","unstructured":"Busch JI, Martinez-Lage M, Ashbridge E, Grossman M, Van Deerlin VM, Hu F, et al. Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain. Acta Neuropathol Commun. 2013;1:36.","journal-title":"Acta Neuropathol Commun"},{"key":"3653_CR58","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1093\/hmg\/dds475","volume":"22","author":"OA Brady","year":"2013","unstructured":"Brady OA, Zheng Y, Murphy K, Huang M, Hu F. The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet. 2013;22:685\u201395.","journal-title":"Hum Mol Genet"},{"key":"3653_CR59","first-page":"2681","volume":"25","author":"JI Busch","year":"2016","unstructured":"Busch JI, Unger TL, Jain N, Tyler Skrinak R, Charan RA, Chen-Plotkin AS. Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes. Hum Mol Genet. 2016;25:2681\u201397.","journal-title":"Hum Mol Genet"},{"key":"3653_CR60","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1002\/embj.201385857","volume":"33","author":"BM Schwenk","year":"2014","unstructured":"Schwenk BM, Lang CM, Hogl S, Tahirovic S, Orozco D, Rentzsch K, et al. The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO J. 2014;33:450\u201367.","journal-title":"EMBO J"},{"key":"3653_CR61","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.mcn.2014.07.006","volume":"61","author":"M Stagi","year":"2014","unstructured":"Stagi M, Klein ZA, Gould TJ, Bewersdorf J, Strittmatter SM. Lysosome size, motility and stress response regulated by fronto-temporal dementia modifier TMEM106B. Mol Cell Neurosci. 2014;61:226\u201340.","journal-title":"Mol Cell Neurosci"},{"key":"3653_CR62","doi-asserted-by":"publisher","first-page":"32298","DOI":"10.1074\/jbc.R112.399170","volume":"287","author":"B Cenik","year":"2012","unstructured":"Cenik B, Sephton CF, Kutluk Cenik B, Herz J, Yu G. Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem. 2012;287:32298\u2013306.","journal-title":"J Biol Chem"},{"key":"3653_CR63","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nrn.2017.36","volume":"18","author":"AW Kao","year":"2017","unstructured":"Kao AW, McKay A, Singh PP, Brunet A, Huang EJ. Progranulin, lysosomal regulation and neurodegenerative disease. Nat Rev Neurosci. 2017;18:325\u201333.","journal-title":"Nat Rev Neurosci"},{"key":"3653_CR64","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00401-018-1861-8","volume":"136","author":"DH Paushter","year":"2018","unstructured":"Paushter DH, Du H, Feng T, Hu F. The lysosomal function of progranulin, a guardian against neurodegeneration. Acta Neuropathol. 2018;136:1\u201317.","journal-title":"Acta Neuropathol"},{"key":"3653_CR65","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1111\/jnc.15378","volume":"158","author":"X Wang","year":"2021","unstructured":"Wang X, Zeng P, Fang Y, Zhang T, Tian Q. Progranulin in neurodegenerative dementia. J Neurochem. 2021;158:119\u201337.","journal-title":"J Neurochem"},{"key":"3653_CR66","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1159\/000447738","volume":"6","author":"LHH Meeter","year":"2016","unstructured":"Meeter LHH, Patzke H, Loewen G, Dopper EGP, Pijnenburg YAL, van Minkelen R, et al. Progranulin levels in plasma and cerebrospinal fluid in granulin mutation carriers. Dement Geriatr Cogn Dis Extra. 2016;6:330\u201340.","journal-title":"Dement Geriatr Cogn Dis Extra"},{"key":"3653_CR67","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/j.ajhg.2017.09.004","volume":"101","author":"MD Gallagher","year":"2017","unstructured":"Gallagher MD, Posavi M, Huang P, Unger TL, Berlyand Y, Gruenewald AL, et al. A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression. Am J Hum Genet. 2017;101:643\u201363.","journal-title":"Am J Hum Genet"},{"key":"3653_CR68","doi-asserted-by":"publisher","first-page":"4055","DOI":"10.1093\/brain\/awad133","volume":"146","author":"C T Vicente","year":"2023","unstructured":"T Vicente C, Perneel J, Wynants S, Heeman B, Van den Broeck M, Baker M, et al. C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes. Brain. 2023;146:4055\u201364.","journal-title":"Brain"},{"key":"3653_CR69","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1007\/s00401-013-1239-x","volume":"127","author":"MD Gallagher","year":"2014","unstructured":"Gallagher MD, Suh E, Grossman M, Elman L, McCluskey L, Van Swieten JC, et al. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol. 2014;127:407\u201318.","journal-title":"Acta Neuropathol"}],"container-title":["Molecular Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41380-026-03653-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-026-03653-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-026-03653-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T09:03:49Z","timestamp":1789117429000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41380-026-03653-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":69,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["3653"],"URL":"https:\/\/doi.org\/10.1038\/s41380-026-03653-w","relation":{},"ISSN":["1359-4184","1476-5578"],"issn-type":[{"value":"1359-4184","type":"print"},{"value":"1476-5578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,18]]},"assertion":[{"value":"29 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 May 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Informed consent was obtained from all subjects involved in this study. This study was conducted according to the guidelines of the Declaration of Helsinki and approved by the local Ethics Committee \u201cComitato Etico IRCCS San Giovanni di Dio Fatebenefratelli\u201d of the IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia (Prot. N. 63\/2022; date of approval: 7 December 2022).","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Not applicable.","order":3,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Ethics"}}]}}