{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T03:32:27Z","timestamp":1769052747564,"version":"3.49.0"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T00:00:00Z","timestamp":1637107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>We have performed whole-genome sequencing to identify the genetic variants potentially contributing to the early-onset semantic dementia phenotype in a patient with family history of dementia and episodic memory deficit accompanied with profound semantic loss. Only very rare variants of unknown significance (VUS) have been identified: a nonsense variant c.366C&gt;A\/p.Cys122* in plasminogen activator, urokinase (PLAU) and a missense variant c.944C&gt;T\/p.Thr315Met in \u03b2-site APP-cleaving enzyme 1 (BACE1)\u2014along with known disease-modifying variants of moderate penetrance. Patient-derived fibroblasts showed reduced PLAU and elevated BACE1 mRNA and protein levels compared to control fibroblasts. Successful rescue of PLAU mRNA levels by nonsense-mediated mRNA decay (NMD) inhibitor (puromycin) confirmed NMD as the underlying mechanism. This is the first report of the PLAU variant with the confirmed haploinsufficiency, associated with semantic dementia phenotype. Our results suggest that rare variants in the PLAU and BACE1 genes should be considered in future studies on early-onset dementias.<\/jats:p>","DOI":"10.3390\/genes12111806","type":"journal-article","created":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T09:16:11Z","timestamp":1637140571000},"page":"1806","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Two Rare Variants in PLAU and BACE1 Genes\u2014Do They Contribute to Semantic Dementia Clinical Phenotype?"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8670-1200","authenticated-orcid":false,"given":"Katarzyna","family":"Gaweda-Walerych","sequence":"first","affiliation":[{"name":"Laboratory of Neurogenetics, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4141-072X","authenticated-orcid":false,"given":"Emilia J.","family":"Sitek","sequence":"additional","affiliation":[{"name":"Neurology Department, St. Adalbert Hospital, Copernicus PL, 80-462 Gdansk, Poland"},{"name":"Division of Neurological and Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdansk, 80-462 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma\u0142gorzata","family":"Borczyk","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacogenomics, Department of Molecular Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 31-343 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2076-4318","authenticated-orcid":false,"given":"Mariusz","family":"Berdy\u0144ski","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ewa","family":"Naro\u017ca\u0144ska","sequence":"additional","affiliation":[{"name":"Neurology Department, St. Adalbert Hospital, Copernicus PL, 80-462 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bogna","family":"Brockhuis","sequence":"additional","affiliation":[{"name":"Division of Nuclear Medicine, Faculty of Health Sciences, Medical University of Gdansk, 80-214 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micha\u0142","family":"Korosty\u0144ski","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacogenomics, Department of Molecular Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 31-343 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaros\u0142aw","family":"S\u0142awek","sequence":"additional","affiliation":[{"name":"Neurology Department, St. Adalbert Hospital, Copernicus PL, 80-462 Gdansk, Poland"},{"name":"Division of Neurological and Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdansk, 80-462 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7332-8494","authenticated-orcid":false,"given":"Cezary","family":"Zekanowski","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.trci.2016.09.002","article-title":"Multiple comorbid neuropathologies in the setting of Alzheimer\u2019s disease neuropathology and implications for drug development","volume":"3","author":"Rabinovici","year":"2017","journal-title":"Alzheimer\u2019s Dement"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1159\/000113679","article-title":"Neuropathological aspects of Alzheimer disease, Parkinson disease and frontotemporal dementia","volume":"5","author":"Jellinger","year":"2008","journal-title":"Neurodegener. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a003491","DOI":"10.1101\/mcs.a003491","article-title":"Genome sequencing for early-onset or atypical dementia: High diagnostic yield and frequent observation of multiple contributory alleles","volume":"5","author":"Cochran","year":"2019","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1186\/s13059-016-1107-9","article-title":"The continuum of causality in human genetic disorders","volume":"17","author":"Katsanis","year":"2016","journal-title":"Genome Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","article-title":"A simple salting out procedure for extracting DNA from human nucleated cells","volume":"16","author":"Miller","year":"1988","journal-title":"Nucleic Acids Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R84","DOI":"10.1186\/gb-2014-15-6-r84","article-title":"LUMPY: A probabilistic framework for structural variant discovery","volume":"15","author":"Layer","year":"2014","journal-title":"Genome Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"giz040","DOI":"10.1093\/gigascience\/giz040","article-title":"Duphold: Scalable, depth-based annotation and curation of high-confidence structural variant calls","volume":"8","author":"Pedersen","year":"2019","journal-title":"Gigascience"},{"key":"ref_8","doi-asserted-by":"crossref","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":"Mackenzie","year":"2011","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1159\/000070999","article-title":"Mutation screening of the MAPT and STH genes in Polish patients with clinically diagnosed frontotemporal dementia","volume":"16","author":"Zekanowski","year":"2003","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/nature05016","article-title":"Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17","volume":"442","author":"Baker","year":"2006","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"676478","DOI":"10.3389\/fnmol.2021.676478","article-title":"Parkin Levels Decrease in Fibroblasts With Progranulin (PGRN) Pathogenic Variants and in a Cellular Model of PGRN Deficiency","volume":"14","author":"Walerych","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.gene.2017.10.048","article-title":"The SMN1 common variant c.22 dupA in Chinese patients causes spinal muscular atrophy by nonsense-mediated mRNA decay in humans","volume":"644","author":"Bai","year":"2018","journal-title":"Gene"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.mrfmmm.2017.09.005","article-title":"p.Val19Glyfs*21 and p.Leu228* variants in the survival of motor neuron 1 trigger nonsense-mediated mRNA decay causing the SMN1 PTC+ transcripts degradation","volume":"806","author":"Qu","year":"2017","journal-title":"Mutat. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_15","first-page":"244","article-title":"Ot\u0119pienie semantyczne\u2014Charakterystyka kliniczna ze szczeg\u00f3lnym uwzgl\u0119dnieniem neuropsychologicznego profilu objaw\u00f3w [Semantic dementia\u2013Clinical characteristics with special emphasis on neuropsychological pattern of symptoms]","volume":"16","author":"Sitek","year":"2020","journal-title":"Polski Przegl\u0105d Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1080\/02687038.2014.904498","article-title":"The patterns of progression in primary progressive aphasia-implications for assessment and management","volume":"28","author":"Harciarek","year":"2014","journal-title":"Aphasiology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1093\/brain\/awv387","article-title":"On the right side? A longitudinal study of left- versus right-lateralized semantic dementia","volume":"139","author":"Kumfor","year":"2016","journal-title":"Brain"},{"key":"ref_18","doi-asserted-by":"crossref","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":"ref_19","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.trci.2016.02.003","article-title":"The ALFA project: A research platform to identify early pathophysiological features of Alzheimer\u2019s disease","volume":"2","author":"Molinuevo","year":"2016","journal-title":"Alzheimer\u2019s Dement"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.biopsych.2020.02.001","article-title":"The beta-Secretase BACE1 in Alzheimer\u2019s Disease","volume":"89","author":"Hampel","year":"2021","journal-title":"Biol. Psychiatry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s13195-016-0219-5","article-title":"An update on semantic dementia: Genetics, imaging, and pathology","volume":"8","author":"Tan","year":"2016","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1093\/brain\/awaa225","article-title":"A clinical-radiological framework of the right temporal variant of frontotemporal dementia","volume":"143","author":"Groot","year":"2020","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1212\/WNL.0b013e31821103e6","article-title":"Classification of primary progressive aphasia and its variants","volume":"76","author":"Hillis","year":"2011","journal-title":"Neurology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1212\/WNL.51.6.1546","article-title":"Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria","volume":"51","author":"Neary","year":"1998","journal-title":"Neurology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1093\/brain\/awp248","article-title":"Semantic dementia: Demography, familial factors and survival in a consecutive series of 100 cases","volume":"133","author":"Hodges","year":"2010","journal-title":"Brain"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.3233\/JAD-201191","article-title":"The Right Temporal Variant of Frontotemporal Dementia Is Not Genetically Sporadic: A Case Series","volume":"79","author":"Nijmeijer","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"497","DOI":"10.3109\/21678421.2015.1074700","article-title":"Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations","volume":"16","author":"Snowden","year":"2015","journal-title":"Amyotroph. Lateral. Scler. Front. Degener."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.eplepsyres.2019.02.009","article-title":"Deficiency of urokinase-type plasminogen activator and its receptor affects social behavior and increases seizure susceptibility","volume":"151","author":"Kyyriainen","year":"2019","journal-title":"Epilepsy Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.yebeh.2014.11.001","article-title":"Urokinase-type plasminogen activator deficiency has little effect on seizure susceptibility and acquired epilepsy phenotype but reduces spontaneous exploration in mice","volume":"42","author":"Rantala","year":"2015","journal-title":"Epilepsy Behav."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1093\/hmg\/ddi041","article-title":"Elevated amyloid beta protein (Abeta42) and late onset Alzheimer\u2019s disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene","volume":"14","author":"Ronald","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Juncker-Jensen, A., and Lund, L.R. (2011). Phenotypic overlap between MMP-13 and the plasminogen activation system during wound healing in mice. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016954"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E1289","DOI":"10.1073\/pnas.1710329115","article-title":"Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer\u2019s disease","volume":"115","author":"Bennett","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1093\/hmg\/ddl167","article-title":"A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer\u2019s disease","volume":"15","author":"Riemenschneider","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/ajmg.b.30103","article-title":"No association of a non-synonymous PLAU polymorphism with Alzheimer\u2019s disease and disease-related traits","volume":"132B","author":"Papassotiropoulos","year":"2005","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s10048-004-0203-2","article-title":"The urokinase-plasminogen activator (PLAU) gene is not associated with late onset Alzheimer\u2019s disease","volume":"6","author":"Bagnoli","year":"2005","journal-title":"Neurogenetics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/0167-4838(95)00228-6","article-title":"Characterization of single chain urokinase-type plasminogen activator with a novel amino-acid substitution in the kringle structure","volume":"1293","author":"Yoshimoto","year":"1996","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Vilarino-Guell, C., Zimprich, A., Martinelli-Boneschi, F., Herculano, B., Wang, Z., Matesanz, F., Urcelay, E., Vandenbroeck, K., Leyva, L., and Gris, D. (2019). Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1008180"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.arr.2018.07.004","article-title":"Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases","volume":"47","author":"Cardoso","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1002\/gps.4423","article-title":"Amyloid deposition in semantic dementia: A positron emission tomography study","volume":"31","author":"Brown","year":"2016","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s40478-021-01229-z","article-title":"Right temporal variant frontotemporal dementia is pathologically heterogeneous: A case-series and a systematic review","volume":"9","author":"Ulugut","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"302","DOI":"10.3389\/fnmol.2017.00302","article-title":"BACE1-Dependent Neuregulin-1 Signaling: An Implication for Schizophrenia","volume":"10","author":"Zhang","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1002\/mdc3.12397","article-title":"Dystonia in a Patient with Autosomal-Dominant Progressive External Ophthalmoplegia Type 1 Caused by Mutation in the POLG Gene","volume":"4","author":"Rossi","year":"2017","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s00401-005-1047-z","article-title":"Alzheimer pathology associated with POLG1 mutation, multiple mtDNA deletions, and APOE4\/4: Premature ageing or just coincidence?","volume":"110","author":"Melberg","year":"2005","journal-title":"Acta Neuropathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1093\/brain\/awy146","article-title":"Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated","volume":"141","author":"Robinson","year":"2018","journal-title":"Brain"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"327","DOI":"10.3389\/fnagi.2019.00327","article-title":"The MAPT H1 Haplotype Is a Risk Factor for Alzheimer\u2019s Disease in APOE epsilon4 Non-carriers","volume":"11","author":"Moreno","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s12687-017-0324-6","article-title":"Readability of informed consent forms for whole-exome and whole-genome sequencing","volume":"9","author":"Niemiec","year":"2018","journal-title":"J. Community Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/11\/1806\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:31:33Z","timestamp":1760167893000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/11\/1806"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,17]]},"references-count":47,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["genes12111806"],"URL":"https:\/\/doi.org\/10.3390\/genes12111806","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,17]]}}}