PSEN2 (presenilin 2 (Alzheimer disease 4))

2010-04-01 Morgan Newman Affiliation

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

Identity

HGNC

PSEN2

LOCATION

1q42.13

LOCUSID

5664

ALIAS

AD3L,AD4,CMD1V,PS2,STM2

FUSION GENES

Show Gene Fusions

DNA/RNA

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

Description

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.

Transcription

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

Pseudogene

Not known.

Proteins

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

Description

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.

Expression

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).

Localisation

Endoplasmic reticulum, plasma membrane, golgi apparatus.

Function

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.

Homology

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

Mutations

Somatic

23 mutations.

Nucleotide change	Disease	Reference
Arg62His	AD	Cruts et al., 1998; Guerreiro et al., 2008
Arg71Trp	AD	Guerreiro et al., 2008
Thr122Pro	AD	Finckh et al., 2000; 2005
Ser130Leu	AD	Sorbi et al., 2002; Tedde et al., 2003; Tomaino et al., 2007
Val139Met	AD	Bernardi et al., 2008
Asn141Ile	AD	Levy-Lahad et al., 1995; Rogaev et al., 1995
Met174Val	AD	Guerreiro et al., 2008
Ser175Cys	AD	Piscopo et al., 2008
Gln228Leu	AD	Zekanowski et al., 2003
Met239Ile	AD	Finckh et al., 2000
Met239Val	AD	Rogaev et al., 1995; Marcon et al., 2004
Val393Met	AD	Lindquist et al., 2008; 2009
Thr430Met	AD	Lleo et al., 2002; Ezquerra et al., 2003
Asp439Ala	AD	Lleo et al., 2001; 2002
Arg62His	Breast Cancer	To et al., 2006
Arg71Trp	Breast Cancer	To et al., 2006
Tyr231Cys	FTD	Marcon et al., 2008; 2009
Ala85Val	LBD	Piscopo et al., 2008
Thr122Arg	Atypical Dementia	Binetti 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

Disease

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.

Oncogenesis

Mutations (see above).

Entity name

Alzheimers disease

Note

Mutations (see above) taken from the Alzheimers Disease and Frontotemporal Dementia Mutation Database. Only pathogenic mutations are included.

Disease

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.

Diagram taken from http://www.molgen.ua.ac.be/ADMutations. Coloured circles indicate mutation sites. Red: pathogenic, orange: pathogenic nature unclear, green: not pathogenic.

Entity name

Frontotemporal Dementia (FTD)

Note

Mutation (see above).

Disease

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)

Note

Mutation (see above).

Disease

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.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
18350357	2008	Late onset familial Alzheimer's disease: novel presenilin 2 mutation and PS1 E318G polymorphism.	Bernardi L et al
14681895	2003	Atypical dementia associated with a novel presenilin-2 mutation.	Binetti G et al
18608129	2008	Molecular genetics of Alzheimer's disease: an update.	Brouwers N et al
9920359	1998	Molecular genetics of Alzheimer's disease.	Cruts M et al
9384602	1998	Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease.	Cruts M et al
12925374	2003	A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease.	Ezquerra M et al
10822446	2000	Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I.	Finckh U et al
15776278	2005	Novel mutations and repeated findings of mutations in familial Alzheimer disease.	Finckh U et al
10631141	2000	High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.	Finckh U et al
12424519	2002	Identification of a second presenilin gene in zebrafish with similarity to the human Alzheimer's disease gene presenilin2.	Groth C et al
18667258	2010	Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP.	Guerreiro RJ et al
10732806	1998	A 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
8922407	1996	Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues.	Lee MK et al
8661049	1996	Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer disease gene.	Levy-Lahad E et al
19659892	2009	Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort.	Lindquist SG et al
12433263	2002	Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain.	Lleó A et al
15055444	2004	Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene.	Marcon G et al
8918895	1996	Neuronal expression of STM2 mRNA in human brain is reduced in Alzheimer's disease.	McMillan PJ et al
12941610	2003	Developmental control of Presenilin1 expression, endoproteolysis, and interaction in zebrafish embryos.	Nornes S et al
19563801	2009	Independent and cooperative action of Psen2 with Psen1 in zebrafish embryos.	Nornes S et al
18427071	2008	A novel PSEN2 mutation associated with a peculiar phenotype.	Piscopo P et al
8904781	1996	Structure and alternative splicing of the presenilin-2 gene.	Prihar G et al
7651536	1995	Familial 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
10349860	1999	A novel presenilin-2 splice variant in human Alzheimer's disease brain tissue.	Sato N et al
15306129	2004	Expression of truncated presenilin 2 splice variant in Alzheimer's disease, bipolar disorder, and schizophrenia brain cortex.	Smith MJ et al
14623725	2003	Identification of new presenilin gene mutations in early-onset familial Alzheimer disease.	Tedde A et al
16474849	2006	Functional characterization of novel presenilin-2 variants identified in human breast cancers.	To MD et al
17345043	2007	Presenilin 2 Ser130Leu mutation in a case of late-onset "sporadic" Alzheimer's disease.	Tomaino C et al
8939861	1996	Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation.	Wolozin B et al
14769392	2003	Mutations 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

Variants:

dbSNP: 5664
ClinVar: 5664
TCGA: ENSG00000143801
COSMIC: PSEN2

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000143801	ENST00000366782	B1AP22
ENSG00000143801	ENST00000366783	P49810
ENSG00000143801	ENST00000422240	P49810
ENSG00000143801	ENST00000460775	E5RFW4
ENSG00000143801	ENST00000472139	E5RG63
ENSG00000143801	ENST00000495488	E5RHT1
ENSG00000143801	ENST00000524196	E5RJM5
ENSG00000143801	ENST00000626989	B1AP22

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Notch signaling pathway	KEGG	ko04330
Alzheimer's disease	KEGG	ko05010
Notch signaling pathway	KEGG	hsa04330
Alzheimer's disease	KEGG	hsa05010
Neurotrophin signaling pathway	KEGG	ko04722
Neurotrophin signaling pathway	KEGG	hsa04722
Notch signaling	KEGG	hsa_M00682
Notch signaling	KEGG	M00682
Disease	REACTOME	R-HSA-1643685
Diseases of signal transduction	REACTOME	R-HSA-5663202
Signaling by NOTCH1 in Cancer	REACTOME	R-HSA-2644603
Signaling by NOTCH1 PEST Domain Mutants in Cancer	REACTOME	R-HSA-2644602
Constitutive Signaling by NOTCH1 PEST Domain Mutants	REACTOME	R-HSA-2644606
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	REACTOME	R-HSA-2894858
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	REACTOME	R-HSA-2894862
Signal Transduction	REACTOME	R-HSA-162582
Signalling by NGF	REACTOME	R-HSA-166520
p75 NTR receptor-mediated signalling	REACTOME	R-HSA-193704
Cell death signalling via NRAGE, NRIF and NADE	REACTOME	R-HSA-204998
NRIF signals cell death from the nucleus	REACTOME	R-HSA-205043
Regulated proteolysis of p75NTR	REACTOME	R-HSA-193692
Signaling by ERBB4	REACTOME	R-HSA-1236394
Nuclear signaling by ERBB4	REACTOME	R-HSA-1251985
Signaling by NOTCH	REACTOME	R-HSA-157118
Signaling by NOTCH1	REACTOME	R-HSA-1980143
Activated NOTCH1 Transmits Signal to the Nucleus	REACTOME	R-HSA-2122948
Signaling by NOTCH2	REACTOME	R-HSA-1980145
NOTCH2 Activation and Transmission of Signal to the Nucleus	REACTOME	R-HSA-2979096
Signaling by NOTCH3	REACTOME	R-HSA-1980148
Signaling by NOTCH4	REACTOME	R-HSA-1980150
Developmental Biology	REACTOME	R-HSA-1266738
Axon guidance	REACTOME	R-HSA-422475
EPH-Ephrin signaling	REACTOME	R-HSA-2682334
EPH-ephrin mediated repulsion of cells	REACTOME	R-HSA-3928665

References

Pubmed ID	Year	Title	Citations
38156414	2024	Quantitative comparison of presenilin protein expression reveals greater activity of PS2-γ-secretase.	0
38227890	2024	Presenilin Gene Mutation-associated Psychosis: Phenotypic Characteristics and Clinical Implications.	0
38156414	2024	Quantitative comparison of presenilin protein expression reveals greater activity of PS2-γ-secretase.	0
38227890	2024	Presenilin Gene Mutation-associated Psychosis: Phenotypic Characteristics and Clinical Implications.	0
35949106	2023	Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease.	4
36217304	2023	The associations of APP, PSEN1, and PSEN2 genes with Alzheimer's disease: A large case-control study in Chinese population.	2
36944398	2023	Different transmembrane domains determine the specificity and efficiency of the cleavage activity of the γ-secretase subunit presenilin.	0
37864790	2023	Cerebral organoids derived from patients with Alzheimer's disease with PSEN1/2 mutations have defective tissue patterning and altered development.	6
35949106	2023	Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease.	4
36217304	2023	The associations of APP, PSEN1, and PSEN2 genes with Alzheimer's disease: A large case-control study in Chinese population.	2
36944398	2023	Different transmembrane domains determine the specificity and efficiency of the cleavage activity of the γ-secretase subunit presenilin.	0
37864790	2023	Cerebral organoids derived from patients with Alzheimer's disease with PSEN1/2 mutations have defective tissue patterning and altered development.	6
34987110	2022	Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis.	6
35491795	2022	PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer's Disease: Data from PUMCH Dementia Cohort.	2
34987110	2022	Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis.	6

Citation

Morgan Newman

PSEN2 (presenilin 2 (Alzheimer disease 4))

Atlas Genet Cytogenet Oncol Haematol. 2010-04-01

Online version: http://atlasgeneticsoncology.org/gene/41883/psen2-(presenilin-2-(alzheimer-disease-4))