{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:02:04Z","timestamp":1760241724270,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2018,9,2]],"date-time":"2018-09-02T00:00:00Z","timestamp":1535846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2017R1A2B4012636","2017R1C1B5017807"],"award-info":[{"award-number":["2017R1A2B4012636","2017R1C1B5017807"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>An in depth study of PSEN1 mutation p.Thr116Ile (c.335C&gt;T) is presented from two Korean families with autosomal dominant inheritance. Clinical manifestation of our patients included memory loss, attention deficits, visuospatial dysfunction, agnosia, aphasia, apraxia, and personality changes, which occurred in their 30s. PSEN1 Thr116Ile was initially discovered in an Italian patient and two French families with early onset Alzheimer\u2019s disease (EOAD) with similar age of onset. To verify the possible pathogenic mechanisms of mutation, in silico predictions and 3D modeling were performed. Structure predictions revealed significant aberrations in first hydrophilic loop (HL-I loop). The hydrophobic isoleucine could alter the loop orientation through increased hydrophobic contacts with the surrounding amino acids. Mutation could destroy a possible hydrogen bond between tyrosine 115 and threonine 116, which may affect the loop conformation. HL-I was confirmed as a conservative region of PSEN1, which may be critical in PSEN1 functions. An additional pathogenic mutation, PSEN1 Thr116Asn, was also found for the same residue, where the patient presented young onset AD (YOND). Other mutations in HL-I loop, such as Tyr115His and Glu120Asp, were described in patients with YOND, supporting the critical role of HL-I loop in PSEN1 activity.<\/jats:p>","DOI":"10.3390\/ijms19092604","type":"journal-article","created":{"date-parts":[[2018,9,3]],"date-time":"2018-09-03T10:50:51Z","timestamp":1535971851000},"page":"2604","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["PSEN1 p.Thr116Ile Variant in Two Korean Families with Young Onset Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0487-8668","authenticated-orcid":false,"given":"Eva","family":"Bagyinszky","sequence":"first","affiliation":[{"name":"Department of Bionano Technology, Gachon University, Sungnam 13120, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4952-5521","authenticated-orcid":false,"given":"Hye-Mi","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology, Korea University Guro Hosipital, Korea University, Seoul 08308, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9937-7865","authenticated-orcid":false,"given":"Vo","family":"Van Giau","sequence":"additional","affiliation":[{"name":"Department of Bionano Technology, Gachon University, Sungnam 13120, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seong-Beom","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Neurology, Korea University Guro Hosipital, Korea University, Seoul 08308, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jee Hyang","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University, Seoul 07985, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seong Soo A.","family":"An","sequence":"additional","affiliation":[{"name":"Department of Bionano Technology, Gachon University, Sungnam 13120, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SangYun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University College of Medicine &amp; Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Sungnam 13620, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.2147\/CIA.S51571","article-title":"The genetics of Alzheimer\u2019s disease","volume":"9","author":"Bagyinszky","year":"2014","journal-title":"Clin. Interv. Aging"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1515\/bc.2010.086","article-title":"Structure, mechanism and inhibition of gamma-secretase and presenilin-like proteases","volume":"391","author":"Wolfe","year":"2010","journal-title":"Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.conb.2017.12.018","article-title":"Presynaptic endocytic factors in autophagy and neurodegeneration","volume":"48","author":"Kuijpers","year":"2018","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1126\/science.1168979","article-title":"A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis","volume":"323","author":"Catania","year":"2009","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"291862","DOI":"10.1155\/2014\/291862","article-title":"Clinical genetics of Alzheimer\u2019s disease","volume":"2014","author":"Zou","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.ncl.2007.03.009","article-title":"Genetics of Alzheimer\u2019s disease: A centennial review","volume":"25","year":"2007","journal-title":"Neurol. Clin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1093\/hmg\/4.12.2373","article-title":"Mutations of the presenilin I gene in families with early-onset Alzheimer\u2019s disease","volume":"4","author":"Campion","year":"1995","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1086\/302553","article-title":"Early-onset autosomal dominant Alzheimer disease: Prevalence, genetic heterogeneity, and mutation spectrum","volume":"65","author":"Campion","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.neuron.2015.02.010","article-title":"Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer\u2019s disease","volume":"85","author":"Xia","year":"2015","journal-title":"Neuron"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1038\/emboj.2012.79","article-title":"The mechanism of \u03b3-secretase dysfunction in familial Alzheimer disease","volume":"31","author":"Bammens","year":"2012","journal-title":"EMBO J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.2147\/CIA.S116724","article-title":"A genetic screen of the mutations in the Korean patients with early-onset Alzheimer\u2019s disease","volume":"11","author":"An","year":"2016","journal-title":"Clin. Interv. Aging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1111\/j.1468-1331.2004.00828.x","article-title":"A novel mutation (Thr116Ile) in the presenilin 1 gene in a patient with early-onset Alzheimer\u2019s disease","volume":"11","author":"Liguori","year":"2004","journal-title":"Eur. J. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1136\/jmg.2005.033456","article-title":"Molecular diagnosis of autosomal dominant early onset Alzheimer\u2019s disease: An update","volume":"42","author":"Raux","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"847","DOI":"10.3233\/JAD-2012-120172","article-title":"The French series of autosomal dominant early onset Alzheimer\u2019s disease cases: Mutation spectrum and cerebrospinal fluid biomarkers","volume":"30","author":"Wallon","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1097\/00001756-199908020-00006","article-title":"A presenilin-1 Thr116Asn substitution in a family with early-onset Alzheimer\u2019s disease","volume":"10","author":"Romero","year":"1999","journal-title":"Neuroreport"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1086\/301672","article-title":"A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease","volume":"62","author":"Tysoe","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1481.e7","DOI":"10.1016\/j.neurobiolaging.2011.12.007","article-title":"Genetic testing in familial and young-onset Alzheimer\u2019s disease: Mutation spectrum in a serbian cohort","volume":"33","author":"Dobricic","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s10048-005-0211-x","article-title":"Novel mutations and repeated findings of mutations in familial Alzheimer disease","volume":"6","author":"Finckh","year":"2005","journal-title":"Neurogenetics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1212\/WNL.55.10.1577","article-title":"Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation","volume":"55","author":"Raux","year":"2000","journal-title":"Neurology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1097\/00001756-199801260-00008","article-title":"A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer\u2019s disease and leads to death as early as the age of 28 years","volume":"9","author":"Wisniewski","year":"2008","journal-title":"Neuroreport"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1093\/hmg\/7.1.43","article-title":"Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease","volume":"7","author":"Cruts","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/(SICI)1098-1004(1998)11:3<216::AID-HUMU6>3.0.CO;2-F","article-title":"Missense mutations in the chromosome 14 familial Alzheimer\u2019s disease presenilin 1 gene","volume":"11","author":"Poorkaj","year":"1998","journal-title":"Hum. Mutat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1136\/jnnp.2007.123026","article-title":"Ataxic variant of Alzheimer\u2019s disease caused by Pro117Ala PSEN1 mutation","volume":"78","author":"Anheim","year":"2007","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1001\/archneur.56.1.65","article-title":"A pedigree with a novel presenilin 1 mutation at a residue that is not conserved in presenilin 2","volume":"56","author":"Yasuda","year":"1999","journal-title":"Arch. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"38042","DOI":"10.1074\/jbc.M110.132613","article-title":"Mutation analysis of the presenilin 1 N-terminal domain reveals a broad spectrum of gamma-secretase activity toward amyloid precursor protein and other substrates","volume":"285","author":"Gong","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/ng1095-219","article-title":"The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families","volume":"11","author":"Winblad","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1523\/JNEUROSCI.3164-14.2015","article-title":"Cooperative roles of hydrophilic loop 1 and the C-terminus of presenilin 1 in the substrate-gating mechanism of \u03b3-secretase","volume":"35","author":"Sasaki","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1957.e1","DOI":"10.1016\/j.neurobiolaging.2014.02.014","article-title":"Mutational analysis in early-onset familial Alzheimer\u2019s disease in Mainland China","volume":"35","author":"Jiao","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1093\/hmg\/4.12.2373","article-title":"Mutations of the presenilin I gene in families with early-onset Alzheimer\u2019s disease","volume":"4","author":"Campion","year":"1995","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/S0014-4886(03)00384-4","article-title":"Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer\u2019s disease in Poland","volume":"184","author":"Zekanowski","year":"2003","journal-title":"Exp. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S0304-3940(99)00351-1","article-title":"Inhibition of neurite outgrowth by familial Alzheimer\u2019s disease-linked presenilin-1 mutations","volume":"267","author":"Dowjat","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_32","first-page":"13","article-title":"New mutation in the PSEN1 (E120G) gene associated with early onset Alzheimer\u2019s disease","volume":"25","author":"Rey","year":"2010","journal-title":"Neurologia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1097\/00001756-199602290-00029","article-title":"Complete analysis of the presenilin 1 gene in early onset Alzheimer\u2019s disease","volume":"7","author":"Hutton","year":"1996","journal-title":"Neuroreport"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1016\/S1474-4422(16)30193-4","article-title":"Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer\u2019s disease: A case series","volume":"15","author":"Ryan","year":"2016","journal-title":"Lancet. Neurol."},{"key":"ref_35","first-page":"563","article-title":"Linkage analysis of familial Alzheimer disease, using chromosome 21 markers","volume":"48","author":"Schellenberg","year":"1991","journal-title":"Am. J. Hum. Genet."},{"key":"ref_36","first-page":"273","article-title":"Assessment of amyloid \u03b2-protein precursor gene mutations in a large set of familial and sporadic alzheimer disease cases","volume":"51","author":"Tanzi","year":"1992","journal-title":"Am. J. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/S0022-510X(98)00219-6","article-title":"Familial Alzheimer\u2019s disease genes in Japanese","volume":"160","author":"Kamimura","year":"1998","journal-title":"J. Neurol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"234","DOI":"10.3346\/jkms.1998.13.3.234","article-title":"Molecular analysis of prion protein gene (PRNP) in Korean patients with Creutzfeldt-Jakob disease","volume":"13","author":"Jeong","year":"1998","journal-title":"J. Korean Med. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1038\/nature05017","article-title":"Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21","volume":"442","author":"Cruts","year":"2006","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1086\/302256","article-title":"High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands","volume":"64","author":"Rizzu","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1101\/gr.1.1.34","article-title":"PCR-SSCP: A simple and sensitive method for detection of mutations in the genomic DNA","volume":"1","author":"Hayashi","year":"1991","journal-title":"PCR Methods Appl."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Choi, Y., Sims, G.E., Murphy, S., Miller, J.R., and Chan, A.P. (2012). Predicting the functional effect of amino acid substitutions and indels. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046688"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3784","DOI":"10.1093\/nar\/gkg563","article-title":"ExPASy: The proteomics server for in-depth protein knowledge and analysis","volume":"31","author":"Gasteiger","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1038\/nprot.2012.085","article-title":"Template-based protein structure modeling using the RaptorX web server","volume":"7","author":"Wang","year":"2012","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/9\/2604\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:18:26Z","timestamp":1760195906000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/9\/2604"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,2]]},"references-count":46,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2018,9]]}},"alternative-id":["ijms19092604"],"URL":"https:\/\/doi.org\/10.3390\/ijms19092604","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2018,9,2]]}}}