PSEN2 (presenilin 2 (Alzheimer disease 4))
2010-04-01 Morgan Newman AffiliationSchool of Molecular, Biomedical Science, The University of Adelaide, Australia
Identity
HGNC
LOCATION
1q42.13
LOCUSID
ALIAS
AD3L,AD4,CMD1V,PS2,STM2
FUSION GENES
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
Expression (GTEx)
Pathways
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
