PSEN2 (presenilin 2)

Gene

• Entrez ID: 5664
• Gene name: Presenilin 2
• Gene symbol: PSEN2
• Synonyms (NCBI Gene): AD3L, AD4, CMD1V, PS2, STM2
• Chromosome: 1
• Chromosome location: 1q42.13
• Summary: Alzheimer`s disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1 or PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs28936379	A>C,G,T	Pathogenic, not-provided	Coding sequence variant, missense variant, non coding transcript variant
rs28936380	C>G,T	Pathogenic, not-provided	Coding sequence variant, missense variant, non coding transcript variant
rs63749851	A>C	Pathogenic, likely-pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs63749884	G>A	Pathogenic, not-provided	Missense variant, non coding transcript variant, coding sequence variant
rs63750048	C>T	Pathogenic, not-provided	Missense variant, non coding transcript variant, coding sequence variant
rs63750110	A>C	Uncertain-significance, pathogenic, not-provided	Missense variant, non coding transcript variant, coding sequence variant, intron variant
rs63750197	C>T	Likely-benign, pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs63750215	A>T	Pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs63750666	C>T	Pathogenic, not-provided	Missense variant, non coding transcript variant, coding sequence variant, intron variant
rs143912759	C>A,T	Conflicting-interpretations-of-pathogenicity, uncertain-significance	Intron variant, coding sequence variant, non coding transcript variant, missense variant
rs145010538	C>G	Conflicting-interpretations-of-pathogenicity, uncertain-significance	Coding sequence variant, synonymous variant, non coding transcript variant
rs188598190	G>A	Conflicting-interpretations-of-pathogenicity	Missense variant, coding sequence variant, non coding transcript variant
rs200610057	C>T	Conflicting-interpretations-of-pathogenicity, uncertain-significance	Coding sequence variant, synonymous variant, non coding transcript variant
rs202178897	G>A,T	Conflicting-interpretations-of-pathogenicity	Non coding transcript variant, missense variant, coding sequence variant
rs866044092	G>A	Likely-pathogenic, uncertain-significance	Missense variant, coding sequence variant, non coding transcript variant
rs1553268799	TGA>-	Likely-pathogenic	Intron variant, splice donor variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT1269617	hsa-miR-3163	CLIP-seq
MIRT1269618	hsa-miR-4484	CLIP-seq
MIRT1269619	hsa-miR-548an	CLIP-seq
MIRT1269620	hsa-miR-1276	CLIP-seq
MIRT1269621	hsa-miR-183	CLIP-seq
MIRT1269622	hsa-miR-30a	CLIP-seq
MIRT1269623	hsa-miR-30b	CLIP-seq
MIRT1269624	hsa-miR-30c	CLIP-seq
MIRT1269625	hsa-miR-30d	CLIP-seq
MIRT1269626	hsa-miR-30e	CLIP-seq
MIRT1269627	hsa-miR-3663-3p	CLIP-seq
MIRT1269628	hsa-miR-4487	CLIP-seq
MIRT1269629	hsa-miR-4726-3p	CLIP-seq
MIRT1269630	hsa-miR-4727-5p	CLIP-seq
MIRT1269631	hsa-miR-4755-3p	CLIP-seq
MIRT1269632	hsa-miR-548a-3p	CLIP-seq
MIRT1269633	hsa-miR-548e	CLIP-seq
MIRT1269634	hsa-miR-548f	CLIP-seq
MIRT1269635	hsa-miR-764	CLIP-seq
MIRT2079248	hsa-miR-134	CLIP-seq
MIRT2079249	hsa-miR-3118	CLIP-seq
MIRT2079250	hsa-miR-3164	CLIP-seq
MIRT2079251	hsa-miR-4302	CLIP-seq
MIRT2079252	hsa-miR-4519	CLIP-seq
MIRT2079253	hsa-miR-4530	CLIP-seq
MIRT2079254	hsa-miR-4700-3p	CLIP-seq
MIRT2079255	hsa-miR-4773	CLIP-seq
MIRT2457303	hsa-miR-3183	CLIP-seq
MIRT1269627	hsa-miR-3663-3p	CLIP-seq
MIRT2457304	hsa-miR-3925-3p	CLIP-seq
MIRT2457305	hsa-miR-4723-3p	CLIP-seq
MIRT1269629	hsa-miR-4726-3p	CLIP-seq
MIRT1269635	hsa-miR-764	CLIP-seq
MIRT2457306	hsa-miR-766	CLIP-seq
MIRT1269622	hsa-miR-30a	CLIP-seq
MIRT1269623	hsa-miR-30b	CLIP-seq
MIRT1269624	hsa-miR-30c	CLIP-seq
MIRT1269625	hsa-miR-30d	CLIP-seq
MIRT1269626	hsa-miR-30e	CLIP-seq
MIRT1269620	hsa-miR-1276	CLIP-seq
MIRT1269622	hsa-miR-30a	CLIP-seq
MIRT1269623	hsa-miR-30b	CLIP-seq
MIRT1269624	hsa-miR-30c	CLIP-seq
MIRT1269625	hsa-miR-30d	CLIP-seq
MIRT1269626	hsa-miR-30e	CLIP-seq
MIRT2688821	hsa-miR-4477b	CLIP-seq
MIRT1269628	hsa-miR-4487	CLIP-seq
MIRT1269630	hsa-miR-4727-5p	CLIP-seq

Transcription factors

Transcription factor	Regulation	Reference
EGR1	Unknown	14585504

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000139	Component	Golgi membrane	IEA
GO:0000776	Component	Kinetochore	IDA	9298903
GO:0000776	Component	Kinetochore	IEA
GO:0001666	Process	Response to hypoxia	IEA
GO:0005515	Function	Protein binding	IPI	9223340, 10366599, 10748169, 12297508, 21163940, 32814053
GO:0005637	Component	Nuclear inner membrane	IDA	9298903
GO:0005769	Component	Early endosome	IEA
GO:0005783	Component	Endoplasmic reticulum	IDA	15274632
GO:0005783	Component	Endoplasmic reticulum	IEA
GO:0005789	Component	Endoplasmic reticulum membrane	IEA
GO:0005794	Component	Golgi apparatus	IDA	15274632
GO:0005794	Component	Golgi apparatus	IEA
GO:0005813	Component	Centrosome	IDA	9298903
GO:0005886	Component	Plasma membrane	IDA	15274632
GO:0005886	Component	Plasma membrane	TAS
GO:0006508	Process	Proteolysis	IEA
GO:0006509	Process	Membrane protein ectodomain proteolysis	IBA
GO:0006509	Process	Membrane protein ectodomain proteolysis	IDA	15274632
GO:0006509	Process	Membrane protein ectodomain proteolysis	IEA
GO:0007219	Process	Notch signaling pathway	IBA
GO:0007219	Process	Notch signaling pathway	IEA
GO:0007220	Process	Notch receptor processing	IEA
GO:0007220	Process	Notch receptor processing	TAS	15274632
GO:0008021	Component	Synaptic vesicle	IEA
GO:0008233	Function	Peptidase activity	IEA
GO:0016020	Component	Membrane	HDA	19946888
GO:0016020	Component	Membrane	IEA
GO:0016485	Process	Protein processing	IBA
GO:0016485	Process	Protein processing	IDA	15274632, 27608597
GO:0016485	Process	Protein processing	IEA
GO:0016787	Function	Hydrolase activity	IEA
GO:0031965	Component	Nuclear membrane	IEA
GO:0032991	Component	Protein-containing complex	IDA	9632714
GO:0034205	Process	Amyloid-beta formation	IBA
GO:0034205	Process	Amyloid-beta formation	IDA	27608597
GO:0035556	Process	Intracellular signal transduction	IEA
GO:0042500	Function	Aspartic endopeptidase activity, intramembrane cleaving	IBA
GO:0042500	Function	Aspartic endopeptidase activity, intramembrane cleaving	IEA
GO:0042734	Component	Presynaptic membrane	IEA
GO:0042987	Process	Amyloid precursor protein catabolic process	IDA	27608597
GO:0042987	Process	Amyloid precursor protein catabolic process	IEA
GO:0042987	Process	Amyloid precursor protein catabolic process	TAS	15274632
GO:0055074	Process	Calcium ion homeostasis	IBA
GO:0070765	Component	Gamma-secretase complex	IBA
GO:0070765	Component	Gamma-secretase complex	IDA	12297508
GO:0097060	Component	Synaptic membrane	IEA
GO:0110097	Process	Regulation of calcium import into the mitochondrion	IMP	21285369
GO:1990456	Process	Mitochondrion-endoplasmic reticulum membrane tethering	IMP	21285369

Other IDs

• MIM: 600759
• HGNC: 9509
• e!Ensembl: ENSG00000143801

Protein

• UniProt ID: P49810
• Protein name: Presenilin-2 (PS-2) (EC 3.4.23.-) (AD3LP) (AD5) (E5-1) (STM-2) [Cleaved into: Presenilin-2 NTF subunit; Presenilin-2 CTF subunit]
• Protein function: Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Requires the other membe
• PDB: 7Y5X, 7Y5Z
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF01080	Presenilin	82 → 330	Presenilin	Family
  PF01080	Presenilin	319 → 438	Presenilin	Family

• Tissue specificity: TISSUE SPECIFICITY: 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. {ECO:0000269|PubMed:8574969}.
• Sequence:

  MLTFMASDSEEEVCDERTSLMSAESPTPRSCQEGRQGPEDGENTAQWRSQENEEDGEEDP
  DRYVCSGVPGRPPGLEEELTLKYGAKHVIMLFVPVTLCMIVVVATIKSVRFYTEKNGQLI
  YTPFTEDTPSVGQRLLNSVLNTLIMISVIVVMTIFLVVLYKYRCYKFIHGWLIMSSLMLL
  FLFTYIYLGEVLKTYNVAMDYPTLLLTVWNFGAVGMVCIHWKGPLVLQQAYLIMISALMA
  LVFIKYLPEWSAWVILGAISVYDLVAVLCPKGPLRMLVETAQERNEPIFPALIYSSAMVW
  TVGMAKLDPSSQGALQLPYDPEMEEDSYDSFGEPSYPEVFEPPLTGYPGEELEEEEERGV
  KLGLGDFIFYSVLVGKAAATGSGDWNTTLACFVAILIGLCLTLLLLAVFKKALPALPISI
  TFGLIFYFSTDNLVRPFMDTLASHQLYI

• Sequence length: 448

Pathways

KEGG:

Notch signaling pathway
Neurotrophin signaling pathway
Alzheimer disease
Pathways of neurodegeneration - multiple diseases

Reactome:

Nuclear signaling by ERBB4
Regulated proteolysis of p75NTR
NRIF signals cell death from the nucleus
Constitutive Signaling by NOTCH1 PEST Domain Mutants
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
EPH-ephrin mediated repulsion of cells
NOTCH3 Activation and Transmission of Signal to the Nucleus
Noncanonical activation of NOTCH3

Associated diseases

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession
Alzheimer disease 4	Pathogenic; Likely pathogenic	rs63750215, rs28936379, rs63749851, rs63749884, rs28936380, rs63750048, rs1553268799	RCV000009393 RCV000009394 RCV000009397 RCV000009398 RCV000009399 RCV000009402 RCV000552294

Unknown
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession
Acute myeloid leukemia	Likely benign; Benign	rs1800679, rs79822981	RCV005916414 RCV005917250
Alzheimer disease	Benign; Likely benign; Uncertain significance	rs58973334, rs63750110, rs63750197	RCV000172777 RCV000172102 RCV000172588
Cervical cancer	Likely benign; Benign	rs1800679, rs79822981	RCV005916415 RCV005917251
Dilated cardiomyopathy 1V	Benign; Likely benign; Uncertain significance; Conflicting classifications of pathogenicity	rs58973334, rs63750207, rs765144719, rs2855562, rs2802267, rs1295644, rs1295643, rs2236910, rs200410369, rs142892469, rs202005802, rs144277432, rs143501870, rs1302750366, rs202133351, rs140501902, rs63750197, rs11405, rs6759, rs1046240, rs148996705, rs114334281, rs61730652, rs147702142, rs6426553, rs886046061, rs766853710, rs773522773, rs199587016, rs145129440, rs116807339, rs7961, rs145010538, rs756225509, rs753503617, rs571670427, rs143059995, rs186288674, rs12758915, rs6665033, rs1295645, rs75733498, rs886046062, rs7962, rs199532840, rs200607063, rs200610057, rs749301595, rs201399057, rs8383, rs202160009, rs202178897, rs367855127, rs143227762, rs115652716, rs150400387, rs148238688, rs61757781, rs146894466, rs200801915, rs138836272, rs200636353, rs555809980, rs149590162, rs1660571955, rs202003390, rs371562367, rs200326485, rs142690225, rs1387034807, rs756609078, rs201922151, rs199547508, rs200296479, rs199645229, rs200173939, rs201177570	RCV000283560 RCV002490737 RCV002476655 RCV001789464 RCV001789466 RCV001789498 RCV001789506 RCV001789543 RCV001823431 RCV002484755 RCV002494087 RCV002481040 RCV001097368 RCV002465024 RCV000763832 RCV001099114 RCV000009400 RCV000286903 RCV000378064 RCV000394749 RCV001099213 RCV000260833 RCV000266614 RCV000376425 RCV000351210 RCV000315539 RCV000262295 RCV000307757 RCV000338629 RCV000337634 RCV000405292 RCV000375861 RCV000316147 RCV000404043 RCV000298921 RCV000328409 RCV000270923 RCV000389910 RCV000286071 RCV000303976 RCV000364413 RCV000345435 RCV000358812 RCV000358270 RCV000396108 RCV000369997 RCV000368015 RCV000273377 RCV000397853 RCV000386193 RCV000278741 RCV001099214 RCV002490889 RCV001097367 RCV001099323 RCV002485611 RCV002507403 RCV002487885 RCV002507535 RCV001099115 RCV001097461 RCV001101118 RCV001101218 RCV001097290 RCV001099042 RCV001100851 RCV001097457 RCV001097459 RCV001097561 RCV001101313 RCV001101314 RCV001101317 RCV001101319 RCV001101320 RCV001097667 RCV001097668 RCV001099435 RCV001101428
Dilated Cardiomyopathy, Dominant	Likely benign	rs186308126, rs16846619	RCV000404953 RCV000332001
Early-onset autosomal dominant Alzheimer disease	Likely benign	rs186308126, rs16846619	RCV000339828 RCV000386484
Familial cancer of breast	Benign	rs1046240	RCV005891316
Gastric cancer	Likely benign; Benign	rs1800679, rs79822981	RCV005916416 RCV005917252
Huntington disease-like syndrome	Conflicting classifications of pathogenicity	rs866044092	RCV000736268
Lung cancer	Benign	rs79822981	RCV005917253
Primary dilated cardiomyopathy	Conflicting classifications of pathogenicity	rs143501870	RCV000157425
PSEN2-related disorder	Likely benign; Conflicting classifications of pathogenicity; Benign; Uncertain significance	rs144318314, rs1208742830, rs188598190, rs139972151, rs143912759, rs199760083, rs146718524, rs63750197, rs1379056144, rs762674312, rs201093218, rs144629723, rs2527981372, rs766859560, rs1553269834, rs199714082, rs758985161, rs367645069, rs202178897, rs200350640, rs150400387, rs781597971, rs200332829	RCV003980387 RCV003893492 RCV003927573 RCV003416064 RCV004754330 RCV003903794 RCV003916602 RCV003934816 RCV003404296 RCV003391446 RCV003966543 RCV003901273 RCV003896837 RCV003933899 RCV003954944 RCV003949873 RCV003946938 RCV003900078 RCV004754458 RCV003953143 RCV003420219 RCV003948228 RCV004754596
Uterine corpus endometrial carcinoma	Benign	rs79822981	RCV005917254
Vascular dementia	Uncertain significance	rs143061887	RCV001263187

Associations from Text Mining
Disease Name	Relationship Type	References
AA amyloidosis	Associate	11126197, 28243073, 36120786
Agnosia	Associate	33973882
Agraphia	Associate	35491795
Alzheimer Disease	Associate	10349860, 10366599, 10393846, 10404513, 10409650, 10595683, 10620705, 10652366, 10880397, 11126197, 12754354, 15009634, 15492223, 15569262, 15685448, 15975090, 16033913, 16199521, 16371011, 16533963, 17186461, 17314098, 17903177, 18387709, 18437002, 18667258, 20194618, 20333730, 20375137, 20393312, 20457965, 21034535, 21285369, 21411544, 21816272, 22153900, 22166940, 22267728, 22459598, 22503161, 22702962, 23085935, 23183136, 23379308, 23884042, 23902769, 23990795, 24219606, 24363250, 24463146, 24880964, 24885952, 25104557, 25639959, 26139022, 26242991, 26573292, 26888304, 27206484, 27901073, 28008242, 28049728, 28106563, 28243073, 28350801, 28738127, 28749476, 28798312, 28949931, 29045054, 29078389, 29078805, 29141208, 29156377, 29175279, 29182052, 29269939, 29397305, 29476165, 29579160, 29661148, 29880032, 29945658, 30021643, 30045758, 30104866, 30114415, 30549411, 30634129, 30704603, 30822648, 31020001, 31165862, 31182772, 31416668, 31557888, 31861093, 32087291, 32106535, 32977230, 33006056, 33023779, 33188256, 33213512, 33413468, 33440141, 33678657, 33973882, 34067945, 34088008, 34102969, 34319632, 34440738, 34444269, 34634760, 34948396, 34987110, 35065037, 35120450, 35226190, 35246267, 35328387, 35449212, 35491795, 35752680, 35949106, 36120786, 36175824, 36217304, 36251323, 36362122, 36555832, 37108607, 37864790, 37924159, 38178159, 38531230, 39273625, 39322953, 39766777, 39875235, 39903689, 40016812, 40149496, 40363838, 8901624, 8925918, 9110991, 9144240, 9250173, 9275228, 9639678, 9880584
Alzheimer Disease	Stimulate	22312439
Alzheimer disease type 1	Associate	18580586, 30045758, 33678657, 35491795
Amyloid angiopathy	Associate	20375137
Apraxias	Associate	35491795
Asphyxia	Associate	34067945
Atrophy	Associate	26507310, 33973882, 34102969
Autistic Disorder	Inhibit	24853428
CADASIL	Associate	36175824
Cardiomyopathies	Associate	20458009
Cardiomyopathy Dilated	Associate	17186461
Cardiomyopathy Hypertrophic	Associate	28750076, 32344918
Cardiovascular Diseases	Associate	39766777
Cerebral Hemorrhage	Associate	20375137
Cerebral Small Vessel Diseases	Associate	36175824
Cognition Disorders	Associate	35328387
Cognitive Dysfunction	Associate	30104866
Death	Associate	20375137
Dementia	Associate	20375137, 21163230, 21297263, 22312439, 22503161, 24885952, 27901073, 29476165, 29859640, 30530974, 33061333, 33203472, 34444269, 35120450
Depressive Disorder Major	Inhibit	24363250
Disease	Associate	17186461
Dyscalculia	Associate	35491795
Frontotemporal Dementia	Associate	22503161, 35752680
Frontotemporal Lobar Degeneration	Associate	22459598
Genetic Diseases Inborn	Associate	22503161
Genomic Instability	Associate	32397113
Hallucinations	Associate	39273625
Heart Failure	Associate	17186461
Hypoxia	Associate	10349860
Hypoxia Brain	Associate	15569262
Inflammation	Associate	38178159
Intellectual Disability	Associate	35491795
Lewy Body Disease	Associate	31165862, 36362122
Malformations of Cortical Development Group I	Associate	26025363
Malocclusion Angle Class III	Associate	34039391
Melanoma	Associate	39213172
Memory Disorders	Associate	36362122, 39273625
Meningomyelocele	Associate	39774454
Muscle Spasticity	Associate	22503161
Myelodysplastic Syndromes	Associate	32397113
Neoplasms	Associate	24223915
Neurodegenerative Diseases	Associate	17903177, 22489754, 29859640, 36362122
Seizures	Associate	20375137, 22503161
Stomach Neoplasms	Associate	24008668
Ventricular Fibrillation	Associate	29269939
Vision Disorders	Associate	35491795