PSEN2 (presenilin 2 (Alzheimer disease 4))

2010-04-01   Morgan Newman 

School of Molecular, Biomedical Science, The University of Adelaide, Australia




Atlas Image
Presenilin 2 transcript, lines indicate introns and boxes exons. Untranslated regions are represented as yellow boxes and coding regions as red boxes.


Twelve exons, spans approximately 26.7 kb of genomic DNA in the centromere to telomere orientation, the translation initation codon is in exon 4 and the stop codon in exon 12.


mRNA of approximately 2.3 kb. Two alternatively spliced transcript variants encoding different isoforms of PSEN2 have been identified.


Not known.


Atlas Image
Presenilin 2 protein domains, bright blue boxes are transmembrane domains (TM).


The open reading frame encodes a 448 amino acid protein, with an estimated molecular weight of 50 kDa. It is a multi-spanning transmembrane protein with a predicted 9 transmembrane domains. Heterogeneous proteolytic processing generates N-terminal and C-terminal fragments.


Neuronal (higher levels in hippocampus and cerebellum). Isoform 1 is seen in the placenta, skeletal muscle and heart while isoform 2 is seen in the heart, brain, placenta, liver, skeletal muscle and kidney. (In isoform 2 amino-acids 263-296 are missing).


Endoplasmic reticulum, plasma membrane, golgi apparatus.


Catalytic core of the gamma-secretase complex. This complex catalyses the intramembrane cleavage of single-pass membrane proteins such as Notch and the Amyloid Precursor Protein (APP) to give intracellular signaling. The released intracellular domains of Notch or APP form complexes with other proteins to regulate gene transcription.


The PSEN2 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, and zebrafish.



23 mutations.
Nucleotide changeDiseaseReference
Arg62HisADCruts et al., 1998; Guerreiro et al., 2008
Arg71Trp ADGuerreiro et al., 2008
Thr122ProADFinckh et al., 2000; 2005
Ser130LeuADSorbi et al., 2002; Tedde et al., 2003; Tomaino et al., 2007
Val139MetADBernardi et al., 2008
Asn141IleADLevy-Lahad et al., 1995; Rogaev et al., 1995
Met174Val ADGuerreiro et al., 2008
Ser175CysADPiscopo et al., 2008
Gln228Leu ADZekanowski et al., 2003
Met239Ile ADFinckh et al., 2000
Met239ValADRogaev et al., 1995; Marcon et al., 2004
Val393Met ADLindquist et al., 2008; 2009
Thr430MetADLleo et al., 2002; Ezquerra et al., 2003
Asp439AlaADLleo et al., 2001; 2002
Arg62HisBreast CancerTo et al., 2006
Arg71TrpBreast CancerTo et al., 2006
Tyr231Cys FTDMarcon et al., 2008; 2009
Ala85ValLBDPiscopo et al., 2008
Thr122ArgAtypical DementiaBinetti et al., 2003

Table. Mutations identified through genetic screening. AD: Alzheimers Disease, FTD: Frontotemporal Dementia, LBD: Lewy Body Dementia.

Implicated in

Entity name
Breast cancer
Breast cancer is the most common form of cancer for women. The cancer originates from the breast tissue where it can be a ductal carcinoma or lobular carcinoma. They can be further defined as in situ or invasive cancers.
Mutations (see above).
Entity name
Alzheimers disease
Mutations (see above) taken from the Alzheimers Disease and Frontotemporal Dementia Mutation Database. Only pathogenic mutations are included.
Alzheimers disease is the most prevalent form of dementia. In affected individuals the disease causes a progressive and permanent decline in memory and cognitive abilities. Neuropathogenesis is proposed to be a result of the accumulation of amyloid-beta peptides in the brain together with increased oxidative stress and neuroinflammation. The presenilin proteins are central to the gamma-secretase cleavage of the amyloid precursor protein (APP), releasing the amyloid-beta peptide. Point mutations in the presenilin genes lead to cases of familial Alzheimers disease (and some sporadic cases) by altering APP cleavage resulting in excess amyloid-beta formation.
Atlas Image
Diagram taken from Coloured circles indicate mutation sites. Red: pathogenic, orange: pathogenic nature unclear, green: not pathogenic.
Entity name
Frontotemporal Dementia (FTD)
Mutation (see above).
Frontotemporal dementia is a group of related conditions resulting from the progressive degeneration of the temporal and frontal lobes of the brain (frontotemporal lobar degeneration, FTLD), usually with the presence of abnormal intracellular protein accumulations. These areas of the brain play a significant role in decision-making, behavioral control, emotion and language. The disorder is often sporadic, familial FTD has been linked to mutations in several genes, including those encoding the microtubule-associated protein tau (MAPT), progranulin (GRN), valosin-containing protein (VCP) and charged multivescicular body protein 2B (CHMP2B).
Entity name
Lewy body Dementia (DLB)
Mutation (see above).
Dementia with Lewy bodies is a neurodegenerative disorder associated with abnormal structures (Lewy bodies) which are clumps of alpha-synuclein and ubiquitin protein in neurons found in certain areas of the brain. In addition to dementia, patients with dementia with Lewy bodies experience hallucinations, motor impairment, and fluctuating alertness.


Pubmed IDLast YearTitleAuthors
183503572008Late onset familial Alzheimer's disease: novel presenilin 2 mutation and PS1 E318G polymorphism.Bernardi L et al
146818952003Atypical dementia associated with a novel presenilin-2 mutation.Binetti G et al
186081292008Molecular genetics of Alzheimer's disease: an update.Brouwers N et al
99203591998Molecular genetics of Alzheimer's disease.Cruts M et al
93846021998Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease.Cruts M et al
129253742003A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease.Ezquerra M et al
108224462000Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I.Finckh U et al
157762782005Novel mutations and repeated findings of mutations in familial Alzheimer disease.Finckh U et al
106311412000High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.Finckh U et al
124245192002Identification of a second presenilin gene in zebrafish with similarity to the human Alzheimer's disease gene presenilin2.Groth C et al
186672582010Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP.Guerreiro RJ et al
107328061998A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer's disease.Lao JI et al
89224071996Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues.Lee MK et al
86610491996Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer disease gene.Levy-Lahad E et al
196598922009Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort.Lindquist SG et al
124332632002Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain.Lleó A et al
150554442004Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene.Marcon G et al
89188951996Neuronal expression of STM2 mRNA in human brain is reduced in Alzheimer's disease.McMillan PJ et al
129416102003Developmental control of Presenilin1 expression, endoproteolysis, and interaction in zebrafish embryos.Nornes S et al
195638012009Independent and cooperative action of Psen2 with Psen1 in zebrafish embryos.Nornes S et al
184270712008A novel PSEN2 mutation associated with a peculiar phenotype.Piscopo P et al
89047811996Structure and alternative splicing of the presenilin-2 gene.Prihar G et al
76515361995Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.Rogaev EI et al
103498601999A novel presenilin-2 splice variant in human Alzheimer's disease brain tissue.Sato N et al
153061292004Expression of truncated presenilin 2 splice variant in Alzheimer's disease, bipolar disorder, and schizophrenia brain cortex.Smith MJ et al
146237252003Identification of new presenilin gene mutations in early-onset familial Alzheimer disease.Tedde A et al
164748492006Functional characterization of novel presenilin-2 variants identified in human breast cancers.To MD et al
173450432007Presenilin 2 Ser130Leu mutation in a case of late-onset "sporadic" Alzheimer's disease.Tomaino C et al
89398611996Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation.Wolozin B et al
147693922003Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland.Zekanowski C et al

Other Information

Locus ID:

NCBI: 5664
MIM: 600759
HGNC: 9509
Ensembl: ENSG00000143801


dbSNP: 5664
ClinVar: 5664
TCGA: ENSG00000143801


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Notch signaling pathwayKEGGko04330
Alzheimer's diseaseKEGGko05010
Notch signaling pathwayKEGGhsa04330
Alzheimer's diseaseKEGGhsa05010
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Notch signalingKEGGhsa_M00682
Notch signalingKEGGM00682
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by NOTCH1 in CancerREACTOMER-HSA-2644603
Signaling by NOTCH1 PEST Domain Mutants in CancerREACTOMER-HSA-2644602
Constitutive Signaling by NOTCH1 PEST Domain MutantsREACTOMER-HSA-2644606
Signaling by NOTCH1 HD+PEST Domain Mutants in CancerREACTOMER-HSA-2894858
Constitutive Signaling by NOTCH1 HD+PEST Domain MutantsREACTOMER-HSA-2894862
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
p75 NTR receptor-mediated signallingREACTOMER-HSA-193704
Cell death signalling via NRAGE, NRIF and NADEREACTOMER-HSA-204998
NRIF signals cell death from the nucleusREACTOMER-HSA-205043
Regulated proteolysis of p75NTRREACTOMER-HSA-193692
Signaling by ERBB4REACTOMER-HSA-1236394
Nuclear signaling by ERBB4REACTOMER-HSA-1251985
Signaling by NOTCHREACTOMER-HSA-157118
Signaling by NOTCH1REACTOMER-HSA-1980143
Activated NOTCH1 Transmits Signal to the NucleusREACTOMER-HSA-2122948
Signaling by NOTCH2REACTOMER-HSA-1980145
NOTCH2 Activation and Transmission of Signal to the NucleusREACTOMER-HSA-2979096
Signaling by NOTCH3REACTOMER-HSA-1980148
Signaling by NOTCH4REACTOMER-HSA-1980150
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
EPH-Ephrin signalingREACTOMER-HSA-2682334
EPH-ephrin mediated repulsion of cellsREACTOMER-HSA-3928665


Pubmed IDYearTitleCitations
263128282016The genetic landscape of Alzheimer disease: clinical implications and perspectives.153
172685052007Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease.125
223124392012Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families.108
185914292008SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production.105
198340682009Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria.90
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
212853692011Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk.79
172685042007When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease.73
205946212012The genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOE.73
272931892016Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool.72


Morgan Newman

PSEN2 (presenilin 2 (Alzheimer disease 4))

Atlas Genet Cytogenet Oncol Haematol. 2010-04-01

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