GSN

Summary

GSN (gelsolin, HGNC:4620) is a protein-coding gene on chromosome 9q33.2, encoding Gelsolin (P06396). Calcium-regulated, actin-modulating protein that binds to the plus (or barbed) ends of actin monomers or filaments, preventing monomer exchange (end-blocking or capping).

The protein encoded by this gene binds to the “plus” ends of actin monomers and filaments to prevent monomer exchange. The encoded calcium-regulated protein functions in both assembly and disassembly of actin filaments. Defects in this gene are a cause of familial amyloidosis Finnish type (FAF). Multiple transcript variants encoding several different isoforms have been found for this gene.

Source: NCBI Gene 2934 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Finnish type amyloidosis (Definitive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 990 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 57
• Druggable target: yes
• MANE Select transcript: NM_198252

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4620
Approved symbol	GSN
Name	gelsolin
Location	9q33.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp313L0718
Ensembl gene	ENSG00000148180
Ensembl biotype	protein_coding
OMIM	137350
Entrez	2934

Gene structure

Transcript identifiers

Ensembl transcripts: 274 — 267 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000373806, ENST00000373807, ENST00000373808, ENST00000373818, ENST00000373823, ENST00000394353, ENST00000432226, ENST00000434663, ENST00000449733, ENST00000477104, ENST00000477553, ENST00000477863, ENST00000483960, ENST00000485767, ENST00000545652, ENST00000699558, ENST00000900518, ENST00000900519, ENST00000900520, ENST00000900521, ENST00000900522, ENST00000900523, ENST00000900524, ENST00000900525, ENST00000900526, ENST00000900527, ENST00000900528, ENST00000900529, ENST00000900530, ENST00000900531, ENST00000900532, ENST00000900533, ENST00000900534, ENST00000900535, ENST00000900536, ENST00000900537, ENST00000900538, ENST00000900539, ENST00000900540, ENST00000900541, ENST00000900542, ENST00000900543, ENST00000900544, ENST00000900545, ENST00000900546, ENST00000900547, ENST00000900548, ENST00000900549, ENST00000900550, ENST00000900551, ENST00000900552, ENST00000900553, ENST00000900554, ENST00000900555, ENST00000900556, ENST00000900557, ENST00000900558, ENST00000900559, ENST00000900560, ENST00000900561, ENST00000900562, ENST00000900563, ENST00000900564, ENST00000900565, ENST00000900566, ENST00000900567, ENST00000900568, ENST00000900569, ENST00000900570, ENST00000900571, ENST00000900572, ENST00000900573, ENST00000900574, ENST00000900575, ENST00000900576, ENST00000900577, ENST00000900578, ENST00000900579, ENST00000900580, ENST00000900581, ENST00000900582, ENST00000900583, ENST00000900584, ENST00000900585, ENST00000900586, ENST00000900587, ENST00000900588, ENST00000900589, ENST00000900590, ENST00000900591, ENST00000900592, ENST00000900593, ENST00000900594, ENST00000900595, ENST00000900596, ENST00000900597, ENST00000900598, ENST00000900599, ENST00000900600, ENST00000900601, ENST00000900602, ENST00000900603, ENST00000900604, ENST00000900605, ENST00000900606, ENST00000900607, ENST00000900608, ENST00000900609, ENST00000900610, ENST00000900611, ENST00000900612, ENST00000900613, ENST00000900614, ENST00000900615, ENST00000900616, ENST00000900617, ENST00000900618, ENST00000900619, ENST00000900620, ENST00000900621, ENST00000900622, ENST00000900623, ENST00000900624, ENST00000900625, ENST00000900626, ENST00000900627, ENST00000900628, ENST00000900629, ENST00000900630, ENST00000900631, ENST00000900632, ENST00000900633, ENST00000900634, ENST00000900635, ENST00000900636, ENST00000900637, ENST00000900638, ENST00000900639, ENST00000900640, ENST00000900641, ENST00000900642, ENST00000900643, ENST00000900644, ENST00000900645, ENST00000900646, ENST00000917232, ENST00000917233, ENST00000917234, ENST00000917235, ENST00000917236, ENST00000917237, ENST00000917238, ENST00000917239, ENST00000972553, ENST00000972554, ENST00000972555, ENST00000972556, ENST00000972557, ENST00000972558, ENST00000972559, ENST00000972560, ENST00000972561, ENST00000972562, ENST00000972563, ENST00000972564, ENST00000972565, ENST00000972566, ENST00000972567, ENST00000972568, ENST00000972569, ENST00000972570, ENST00000972571, ENST00000972572, ENST00000972573, ENST00000972574, ENST00000972575, ENST00000972576, ENST00000972577, ENST00000972578, ENST00000972579, ENST00000972580, ENST00000972581, ENST00000972582, ENST00000972583, ENST00000972584, ENST00000972585, ENST00000972586, ENST00000972587, ENST00000972588, ENST00000972589, ENST00000972590, ENST00000972591, ENST00000972592, ENST00000972593, ENST00000972594, ENST00000972595, ENST00000972596, ENST00000972597, ENST00000972598, ENST00000972599, ENST00000972600, ENST00000972601, ENST00000972602, ENST00000972603, ENST00000972604, ENST00000972605, ENST00000972606, ENST00000972607, ENST00000972608, ENST00000972609, ENST00000972610, ENST00000972611, ENST00000972612, ENST00000972613, ENST00000972614, ENST00000972615, ENST00000972616, ENST00000972617, ENST00000972618, ENST00000972619, ENST00000972620, ENST00000972621, ENST00000972622, ENST00000972623, ENST00000972624, ENST00000972625, ENST00000972626, ENST00000972627, ENST00000972628, ENST00000972629, ENST00000972630, ENST00000972631, ENST00000972632, ENST00000972633, ENST00000972634, ENST00000972635, ENST00000972636, ENST00000972637, ENST00000972638, ENST00000972639, ENST00000972640, ENST00000972641, ENST00000972642, ENST00000972643, ENST00000972644, ENST00000972645, ENST00000972646, ENST00000972647, ENST00000972648, ENST00000972649, ENST00000972650, ENST00000972651, ENST00000972652, ENST00000972653, ENST00000972654, ENST00000972655, ENST00000972656, ENST00000972657, ENST00000972658, ENST00000972659, ENST00000972660, ENST00000972661, ENST00000972662, ENST00000972663, ENST00000972664, ENST00000972665, ENST00000972666, ENST00000972667, ENST00000972668, ENST00000972669, ENST00000972670, ENST00000972671, ENST00000972672, ENST00000972673

RefSeq mRNA: 36 — MANE Select: NM_198252 NM_000177, NM_001127662, NM_001127663, NM_001127664, NM_001127665, NM_001127666, NM_001127667, NM_001258029, NM_001258030, NM_001353053, NM_001353054, NM_001353055, NM_001353056, NM_001353057, NM_001353058, NM_001353059, NM_001353060, NM_001353061, NM_001353062, NM_001353063, NM_001353064, NM_001353065, NM_001353066, NM_001353067, NM_001353068, NM_001353069, NM_001353070, NM_001353071, NM_001353072, NM_001353073, NM_001353074, NM_001353075, NM_001353076, NM_001353077, NM_001353078, NM_198252

CCDS: CCDS48011, CCDS65118, CCDS6828, CCDS6829, CCDS75890, CCDS75891, CCDS94475

Canonical transcript exons

ENST00000432226 — 18 exons

Exon	Start	End
ENSE00001366497	121281470	121281562
ENSE00001732346	121332434	121332842
ENSE00003558462	121301963	121302167
ENSE00003801469	121302911	121303065
ENSE00003801682	121313934	121314023
ENSE00003802936	121331388	121331448
ENSE00003803153	121318406	121318494
ENSE00003805122	121327308	121327482
ENSE00003805785	121310684	121310845
ENSE00003805949	121324554	121324644
ENSE00003806653	121318665	121318880
ENSE00003806924	121317086	121317218
ENSE00003807263	121329238	121329315
ENSE00003807428	121326512	121326682
ENSE00003807590	121321268	121321401
ENSE00003807865	121312339	121312488
ENSE00003808380	121328891	121329015
ENSE00003904110	121268162	121268219

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 152.7563 / max 2352.2128, expressed in 1765 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98341	95.3485	1749
98348	51.7216	1376
98344	0.9843	305
98340	0.7737	281
98367	0.7364	443
98361	0.4650	198
98343	0.4245	183
98364	0.3827	141
98350	0.3241	148
98362	0.3015	110

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
synovial joint	UBERON:0002217	99.91	gold quality
right atrium auricular region	UBERON:0006631	99.88	gold quality
cardiac atrium	UBERON:0002081	99.87	gold quality
olfactory bulb	UBERON:0002264	99.86	gold quality
saphenous vein	UBERON:0007318	99.85	gold quality
right coronary artery	UBERON:0001625	99.82	gold quality
apex of heart	UBERON:0002098	99.81	gold quality
tibial nerve	UBERON:0001323	99.80	gold quality
pericardium	UBERON:0002407	99.80	gold quality
tendon of biceps brachii	UBERON:0008188	99.80	gold quality
vena cava	UBERON:0004087	99.79	gold quality
dorsal root ganglion	UBERON:0000044	99.77	gold quality
coronary artery	UBERON:0001621	99.76	gold quality
calcaneal tendon	UBERON:0003701	99.76	gold quality
mucosa of stomach	UBERON:0001199	99.75	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.75	gold quality
thoracic aorta	UBERON:0001515	99.74	gold quality
left coronary artery	UBERON:0001626	99.74	gold quality
descending thoracic aorta	UBERON:0002345	99.74	gold quality
peritoneum	UBERON:0002358	99.74	gold quality
omental fat pad	UBERON:0010414	99.74	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.74	gold quality
ascending aorta	UBERON:0001496	99.73	gold quality
lower esophagus	UBERON:0013473	99.73	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.73	gold quality
urethra	UBERON:0000057	99.72	gold quality
aorta	UBERON:0000947	99.72	gold quality
popliteal artery	UBERON:0002250	99.72	gold quality
tibial artery	UBERON:0007610	99.72	gold quality
adipose tissue	UBERON:0001013	99.70	gold quality

Single-cell (SCXA)

Detected in 51 experiment(s), a significant marker in 48.

Experiment	Marker?	Max mean expression
E-MTAB-8322	yes	15907.28
E-HCAD-36	yes	9840.01
E-MTAB-8410	yes	7441.13
E-CURD-122	yes	6018.95
E-HCAD-1	yes	5749.56
E-GEOD-135922	yes	5542.03
E-MTAB-9543	yes	5091.83
E-GEOD-134144	yes	4483.54
E-MTAB-9841	yes	4463.29
E-MTAB-6653	yes	4194.72
E-MTAB-10885	yes	3937.67
E-CURD-126	yes	3785.11
E-CURD-79	yes	3779.29
E-ANND-2	yes	3734.48
E-HCAD-11	yes	3687.76

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
TNFRSF10A	Activation
TNFRSF10B	Activation

Upstream regulators (CollecTRI, top): AR, ATF3, EGR1, ESR1, ESR2, HIF1A, SP1, SRF, TP53

miRNA regulators (miRDB)

22 targeting GSN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-6719-3P	99.29	67.78	1387
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-4680-3P	98.64	68.60	2093
HSA-MIR-4714-5P	97.04	67.76	955

Literature-anchored findings (GeneRIF, showing 40)

• crystal structure: loss of a metal-binding site leads to familial amyloidosis-Finnish type (PMID:11753432)
• functions as a regulator of cell growth and apoptosis (PMID:11925941)
• ATF-1 DNA-binding activity was abundant in breast cancer cells and correlated inversely with gelsolin mRNA levels. This suggests a role for ATF-1 in gelsolin promoter silencing, in contrast to its transactivating effect on various other promoters. (PMID:12027462)
• explores the structure-function relationship of the gelsolin-PPI interaction (PMID:12270712)
• Calcium activation of gelsolin: X-Ray crystallography model of the G4-G6/actin complex. (PMID:12460571)
• Gelsolin suppresses tumorigenicity through inhibiting PKC activation in a human lung cancer cell line, PC10. (PMID:12592377)
• Its reduced expression in bladder cancer is regulated by DNA methylation, histone acetylation and chromatin remodeling. (PMID:12613021)
• A visualization of the Ca2+-dependent activation of this protein by using synchrotron footprinting. (PMID:12655044)
• analysis of domain-binding and calcium-binding sites in gelsolin (PMID:12752443)
• Gelsolin and plasminogen activator inhibitor-1 have roles as Ap3A-binding proteins (PMID:12833632)
• conformational dynamics of ligand-induced structural changes (PMID:12966145)
• structure of the isolated C-terminal half of gelsolin (G4-G6) at 2.0 A resolution in the presence of Ca(2+) ions (PMID:14527664)
• 2.6 A resolution crystal structure of a complex formed between G-actin and gelsolin fragment Met25-Gln160 (PMID:14527665)
• Data suggest that mutations that diminish domain 2 Ca(2+) binding allow furin access to an otherwise protected cleavage site, initiating the proteolytic cascade that leads to gelsolin amyloidogenesis and familial amyloidosis of Finnish type. (PMID:14596804)
• the observed ubiquitous increase of gelsolin in the senescent states of cells and tissues, and the increased sensitivity to apoptosis-induction by gelsolin down-regulation, suggests that it would be partly responsible for age-related apoptosis resistance (PMID:14652020)
• Gelsolin is involved in the apoptotic resistance in senescent human diploid fibroblasts. (PMID:15033777)
• gelsolin protects cells from butyrate-induced apoptosis (PMID:15213223)
• The structure of the N-terminal half of gelsolin bound to actin was studied, as well as its roles in severing, apoptosis, and familial amyloidosis. (PMID:15215896)
• IFNalpha can induce morphological cell changes that are peculiar of apoptosis onset through the caspase-3-mediated cleavage of gelsolin. (PMID:15281090)
• Analysis of major platelet membrane proteins revealed significant increase in gelsolin from patients with homozygous and heterozygous forms of beta-thalassemia. (PMID:15310273)
• model of the N-terminal extension on the surface of the gelsolin molecule, which was unknown previously (PMID:15377282)
• Gelsolin has a role as a regulator of cellular functions [review] (PMID:15526166)
• Gelsolin is partly buried in the lipid bilayer at low pH. The linker regionbetween G3 and G4 is involved in this interaction. Vesicle-bound gelsolin can bind to actin filaments, presumably through barbed end capping. (PMID:15527423)
• features of gelsolin amyloidogenic fragments comprised of residues 173-243 and residues 173-202 were investigated (PMID:15538717)
• Mechanisms of GSN dependent and independent EGF stimulated cell motility were studied in an epithelial cell line. (PMID:15922735)
• The tight interaction between plasma gelsolin and endotoxin/lipopolysaccharide (LPS) affects both gelsolin’s actin binding function and some aspects of the effects of LPS on cells. (PMID:16008344)
• gelsolin functions as a switch that controls E- and N-cadherin conversion via Snail, and demonstrated that its knockdown leads to epithelial-mesenchymal transition in human mammary epithelial cells and possibly to the development of human mammary tumors (PMID:16217750)
• Heparin efficiently accelerates the formation of gelsolin amyloid by enabling intermolecular beta-sheet formation. In addition, heparin accelerated aggregation at both early and late stages of amyloidogenesis (PMID:16475811)
• posttranslational N-myristoylation of tGelsolin does not direct mitochondrial targeting, but this modification is involved in the anti-apoptotic activity of tGelsolin (PMID:16556605)
• higher expression in MCM2 and gelsolin was significantly associated with poorer prognosis in patients with NSCLC, which suggests that higher tumor proliferation and motility may be important in the prognosis of NSCLC (PMID:16882345)
• A functional, cooperative relationship between endogenous N-RAS and gelsolin is identified in colorectal cancer cell lines that correlates with survival. (PMID:17130841)
• These data indicate that actin cytoskeletal dynamics modulate the tyrosine phosphorylation of raft-associated proteins and subsequent downstream signal transduction. (PMID:17178161)
• gelsolin G5 domain inhibits HIV-Vpr-induced T-cell apoptosis by blocking the interaction between Vpr and VDAC (PMID:17254575)
• Calcium induced conformational changes in the G1-2 and G1-3 sub-domains of gelsolin, and the binding affinities for the three type II sites, are reported. (PMID:17258204)
• A new family with Meretoja syndrome is reported. This is the first documented family with Meretoja syndrome in Spain and in the Mediterranean countries. The molecular study shows the same mutation of reported families. (PMID:17534828)
• analysis of distinct sites of interaction that form the calponin: gelsolin complex and two calcium switches that control its activity (PMID:17556051)
• Ardalan-Shoja-Kiuru syndrome, a hereditary gelsolin amyloidosis plus retinitis pigmentosa, is due to a G654A gelsolin mutation. (PMID:17720986)
• TP53 mutations are frequent events in bladder cancer progression and gelsolin relates to TP53 status, tumor staging and clinical outcome. (PMID:17982131)
• These results suggest that Egr-1 may be an important breast cancer marker and that an as yet uncharacterized pathway involved in Egr-1 and gelsolin expression exists which leads to breast cancer cell development. (PMID:18204200)
• Gelsolin levels are actively downregulated in pancreatic cancer and enhanced targeting of gelsolin to the ubiquitin-proteasome pathway is an important contributing factor for this effect. (PMID:18584046)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gsna	ENSDARG00000011459
danio_rerio	gsnb	ENSDARG00000045262
mus_musculus	Gsn	ENSMUSG00000026879
rattus_norvegicus	Gsn	ENSRNOG00000018991
drosophila_melanogaster	Gel	FBGN0010225
caenorhabditis_elegans		WBGENE00010593

Paralogs (7): SCIN (ENSG00000006747), CAPG (ENSG00000042493), VIL1 (ENSG00000127831), AVIL (ENSG00000135407), VILL (ENSG00000136059), FLII (ENSG00000177731), SVIL (ENSG00000197321)

Protein

Protein identifiers

Gelsolin — P06396 (reviewed: P06396)

Alternative names: AGEL, Actin-depolymerizing factor, Brevin

All UniProt accessions (8): P06396, A0A0A0MS51, A0A0A0MT01, A0A0U1RQL8, A0A384MEF1, A0A8V8TND7, Q5T0H8, Q5T0I0

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-regulated, actin-modulating protein that binds to the plus (or barbed) ends of actin monomers or filaments, preventing monomer exchange (end-blocking or capping). It can promote the assembly of monomers into filaments (nucleation) as well as sever filaments already formed. Plays a role in ciliogenesis.

Subunit / interactions. Binds to actin and to fibronectin. Identified in a complex composed of ACTA1, COBL, GSN and TMSB4X. Interacts with the inactive form of EIF2AK2/PKR. Interacts with FLII.

Subcellular location. Cytoplasm. Cytoskeleton Secreted.

Tissue specificity. Phagocytic cells, platelets, fibroblasts, nonmuscle cells, smooth and skeletal muscle cells.

Post-translational modifications. Phosphorylation on Tyr-86, Tyr-409, Tyr-465, Tyr-603 and Tyr-651 in vitro is induced in presence of phospholipids.

Disease relevance. Amyloidosis, hereditary systemic 4, Finnish type (AMYLD4) [MIM:105120] A form of hereditary systemic amyloidosis, a disorder characterized by amyloid deposition in multiple tissues resulting in a wide clinical spectrum. AMYLD4 is due to gelsolin amyloid deposition and is typically characterized by cranial neuropathy and lattice corneal dystrophy. Most patients have modest involvement of internal organs, but severe systemic disease can develop in some individuals causing peripheral polyneuropathy, amyloid cardiomyopathy, and nephrotic syndrome leading to renal failure. AMYLD4 is usually inherited in an autosomal dominant pattern. However, homozygotes with a more severe phenotype have also been reported. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Comprises six structurally related gelsolin-like (G1-G6) domains, that, in a calcium-free environment, are packed together to form a compact globular structure in which the putative actin-binding sequences are not sufficiently exposed to enable binding to occur. Binding calcium may release the connections that join the N- and C-terminal halves of gelsolin, enabling each half to bind actin relatively independently. G1 and G4 bind two Ca(2+) in a type I and in a type II manner. G2, G3, G5 and G6 bind only one Ca(2+) in a type II manner. Type I Ca(2+) binding sites are shared between actin and gelsolin-like repeats G1 and G4. Type I binding governs the strength of interactions between gelsolin and actin by direct participation at the binding interface. Ca(2+) binding to G2 and G6 disrupts the interactions between G2 and G6, releases the C-terminal tail, and induces large interdomain rearrangements that result in the exposure of the F-actin-binding site on G2 and contributes to the activation of gelsolin. Binding to phosphoinositides may inhibit the severing and capping properties of gelsolin.

Similarity. Belongs to the villin/gelsolin family.

Isoforms (4)

UniProt ID	Names	Canonical?
P06396-1	1, Secreted, Plasma	yes
P06396-2	2, Cytoplasmic
P06396-3	3
P06396-4	4

RefSeq proteins (36): NP_000168, NP_001121134, NP_001121135, NP_001121136, NP_001121137, NP_001121138, NP_001121139, NP_001244958, NP_001244959, NP_001339982, NP_001339983, NP_001339984, NP_001339985, NP_001339986, NP_001339987, NP_001339988, NP_001339989, NP_001339990, NP_001339991, NP_001339992, NP_001339993, NP_001339994, NP_001339995, NP_001339996, NP_001339997, NP_001339998, NP_001339999, NP_001340000, NP_001340001, NP_001340002, NP_001340003, NP_001340004, NP_001340005, NP_001340006, NP_001340007, NP_937895* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007122	Villin/Gelsolin	Family
IPR007123	Gelsolin-like_dom	Domain
IPR029006	ADF-H/Gelsolin-like_dom_sf	Homologous_superfamily

Pfam: PF00626

UniProt features (153 total): strand 48, helix 30, binding site 29, turn 8, sequence variant 8, modified residue 7, repeat 6, region of interest 4, splice variant 3, mutagenesis site 3, sequence conflict 3, signal peptide 1, chain 1, compositionally biased region 1, disulfide bond 1

Structure

Experimental structures (PDB)

61 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5FAF	X-RAY DIFFRACTION	1.05
6QW3	X-RAY DIFFRACTION	1.3
6LJE	X-RAY DIFFRACTION	1.4
6LJF	X-RAY DIFFRACTION	1.5
2FH1	X-RAY DIFFRACTION	1.55
3CIP	X-RAY DIFFRACTION	1.6
1KCQ	X-RAY DIFFRACTION	1.65
3CI5	X-RAY DIFFRACTION	1.7
5FAE	X-RAY DIFFRACTION	1.7
5O2Z	X-RAY DIFFRACTION	1.7
1D4X	X-RAY DIFFRACTION	1.75
1NLV	X-RAY DIFFRACTION	1.8
1NM1	X-RAY DIFFRACTION	1.8
4PKG	X-RAY DIFFRACTION	1.8
1NMD	X-RAY DIFFRACTION	1.9
1YAG	X-RAY DIFFRACTION	1.9
6H1F	X-RAY DIFFRACTION	1.9
1C0G	X-RAY DIFFRACTION	2
1ESV	X-RAY DIFFRACTION	2
1P8X	X-RAY DIFFRACTION	2
2FF3	X-RAY DIFFRACTION	2
1T44	X-RAY DIFFRACTION	2
2FF6	X-RAY DIFFRACTION	2.05
1YVN	X-RAY DIFFRACTION	2.1
4PKH	X-RAY DIFFRACTION	2.15
1MDU	X-RAY DIFFRACTION	2.2
1EQY	X-RAY DIFFRACTION	2.3
4PKI	X-RAY DIFFRACTION	2.3
3A5N	X-RAY DIFFRACTION	2.36
5UBO	X-RAY DIFFRACTION	2.39

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P06396-F1	89.76	0.77

Antibody-complex structures (SAbDab): 2 — 4S10, 6H1F

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (29): 92; 93; 124; 136; 141; 143; 162–169; 172; 188–196; 213; 214; 236 …

Post-translational modifications (7): 86, 409, 465, 584, 603, 651, 742

Disulfide bonds (1): 215–228

Mutagenesis-validated functional residues (3):

Position	Phenotype
236	does not result in actin depolymerization activity in absence of calcium. has actin depolymerization activity in absence
697	does not result in actin depolymerization activity in absence of calcium. has actin depolymerization activity in absence
719	does not result in actin depolymerization activity in absence of calcium. has actin depolymerization activity in absence

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-264870	Caspase-mediated cleavage of cytoskeletal proteins
R-HSA-6798695	Neutrophil degranulation
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea
R-HSA-977225	Amyloid fiber formation

MSigDB gene sets: 638 (showing top): BIOCARTA_RHO_PATHWAY, GOBP_POSITIVE_REGULATION_OF_PROTEIN_MATURATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_RESPONSE_TO_MUSCLE_STRETCH, GOBP_CIRCULATORY_SYSTEM_PROCESS, MODULE_255, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_ACTIN_NUCLEATION, GOCC_SECRETORY_GRANULE

GO Biological Process (33): phagocytosis, engulfment (GO:0006911), actin filament organization (GO:0007015), central nervous system development (GO:0007417), actin polymerization or depolymerization (GO:0008154), positive regulation of gene expression (GO:0010628), striated muscle atrophy (GO:0014891), cell projection assembly (GO:0030031), actin filament polymerization (GO:0030041), actin filament depolymerization (GO:0030042), protein destabilization (GO:0031648), response to muscle stretch (GO:0035994), host-mediated suppression of symbiont invasion (GO:0046597), actin filament severing (GO:0051014), barbed-end actin filament capping (GO:0051016), positive regulation of actin nucleation (GO:0051127), actin filament capping (GO:0051693), relaxation of cardiac muscle (GO:0055119), cilium assembly (GO:0060271), cellular response to type II interferon (GO:0071346), cardiac muscle cell contraction (GO:0086003), renal protein absorption (GO:0097017), hepatocyte apoptotic process (GO:0097284), positive regulation of keratinocyte apoptotic process (GO:1902174), regulation of establishment of T cell polarity (GO:1903903), regulation of plasma membrane raft polarization (GO:1903906), regulation of receptor clustering (GO:1903909), positive regulation of protein processing in phagocytic vesicle (GO:1903923), amyloid fibril formation (GO:1990000), vesicle-mediated transport (GO:0016192), cell projection organization (GO:0030030), actin cytoskeleton organization (GO:0030036), positive regulation of apoptotic process (GO:0043065), regulation of podosome assembly (GO:0071801)

GO Molecular Function (8): actin binding (GO:0003779), calcium ion binding (GO:0005509), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), phosphatidylinositol 3-kinase catalytic subunit binding (GO:0036313), myosin II binding (GO:0045159), actin filament binding (GO:0051015), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (19): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), sarcoplasm (GO:0016528), lamellipodium (GO:0030027), actin cap (GO:0030478), secretory granule lumen (GO:0034774), phagocytic vesicle (GO:0045335), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), ficolin-1-rich granule lumen (GO:1904813), podosome (GO:0002102), nucleus (GO:0005634), cytoskeleton (GO:0005856), cortical actin cytoskeleton (GO:0030864)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Apoptotic cleavage of cellular proteins	1
Innate Immune System	1
Sensory processing of sound	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
actin polymerization or depolymerization	2
cytoplasm	2
phagocytosis	1
plasma membrane invagination	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
nervous system development	1
system development	1
actin filament organization	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
striated muscle adaptation	1
muscle atrophy	1
cellular component assembly	1
cell projection organization	1
protein polymerization	1
protein depolymerization	1
regulation of protein stability	1
response to mechanical stimulus	1
innate immune response	1
host-mediated perturbation of symbiont process	1
actin filament-based process	1
actin filament capping	1
actin nucleation	1
regulation of actin nucleation	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
negative regulation of actin filament depolymerization	1
negative regulation of actin filament polymerization	1
relaxation of muscle	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1

Protein interactions and networks

STRING

3114 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GSN	HCLS1	P14317	985
GSN	CTTN	Q14247	985
GSN	PFN4	Q8NHR9	960
GSN	PFN3	P60673	955
GSN	PFN1	P07737	953
GSN	TLN1	Q9Y490	939
GSN	TLN2	Q9Y4G6	936
GSN	WASL	O00401	932
GSN	VCL	P18206	877
GSN	CFL1	P23528	865
GSN	CFL2	Q9Y281	862
GSN	VASP	P50552	854
GSN	WAS	P42768	850
GSN	ACTN1	P12814	837
GSN	PXN	P49023	832

IntAct

805 interactions, top by confidence:

A	B	Type	Score
ACTA1	GSN	psi-mi:“MI:0407”(direct interaction)	0.870
GSN	ACTA1	psi-mi:“MI:0407”(direct interaction)	0.870
ACTA1	DNASE1	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
act1	GSN	psi-mi:“MI:0407”(direct interaction)	0.680
ACTA1	WASL	psi-mi:“MI:0407”(direct interaction)	0.610
AIF1	GSN	psi-mi:“MI:0915”(physical association)	0.560
TRIM23	GSN	psi-mi:“MI:0915”(physical association)	0.560
BCAT1	GSN	psi-mi:“MI:0915”(physical association)	0.560
	GSN	psi-mi:“MI:0915”(physical association)	0.560
CAPN3	GSN	psi-mi:“MI:0915”(physical association)	0.560
CDK2	GSN	psi-mi:“MI:0915”(physical association)	0.560
CDKN1A	GSN	psi-mi:“MI:0915”(physical association)	0.560
COL2A1	GSN	psi-mi:“MI:0915”(physical association)	0.560
COMT	GSN	psi-mi:“MI:0915”(physical association)	0.560
DPYS	GSN	psi-mi:“MI:0915”(physical association)	0.560
HBEGF	GSN	psi-mi:“MI:0915”(physical association)	0.560
FOSL2	GSN	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (284): CFLAR (Affinity Capture-Western), ITCH (Affinity Capture-Western), GSN (Affinity Capture-Western), GSN (Affinity Capture-MS), GSN (Affinity Capture-MS), GSN (Affinity Capture-MS), GSN (Affinity Capture-MS), GSN (Affinity Capture-MS), GSN (Affinity Capture-MS), GSN (Affinity Capture-MS), GSN (Affinity Capture-MS), GSN (Affinity Capture-MS), GSN (Affinity Capture-MS), GSN (Affinity Capture-MS), GSN (Affinity Capture-MS)

ESM2 similar proteins: A0A6B9KZ40, A8XV95, B8ATT7, O65570, O75366, O81644, O81645, O88398, O93510, P02640, P06396, P09327, P10733, P13020, P14885, P20305, P24452, P40121, Q07171, Q0J716, Q0JAD9, Q10L71, Q12792, Q17A58, Q24800, Q27319, Q28046, Q28372, Q29261, Q29297, Q298X4, Q3SX14, Q3SZP7, Q5R7N2, Q5RJR2, Q5ZIV9, Q60604, Q62468, Q67U26, Q68FP1

Diamond homologs: A0A6B9KZ40, A8XV95, B8ATT7, F8WK50, O15195, O61270, O65570, O75366, O81643, O81644, O81645, O88398, O93510, P02640, P06396, P09327, P10733, P13020, P14885, P20305, P24452, P34268, P40121, Q07171, Q0J716, Q0JAD9, Q10L71, Q13045, Q21253, Q24020, Q24800, Q27319, Q28046, Q28372, Q29261, Q29297, Q3SX14, Q3SZP7, Q5ZIV9, Q60604

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
CASP3	“down-regulates activity”	GSN	cleavage
“Caspase 3 complex”	“down-regulates activity”	GSN	cleavage
“Caspase 3 complex”	down-regulates	GSN	cleavage
GSN	“down-regulates quantity”	F-actin_assembly	binding
“1D-myo-inositol 1,4,5-trisphosphate”	“down-regulates activity”	GSN	“chemical inhibition”
“phosphatidylinositol bisphosphate”	“down-regulates activity”	GSN	“chemical inhibition”
calcium(2+)	“up-regulates activity”	GSN	“chemical activation”
PTK2B	“down-regulates activity”	GSN	phosphorylation
TNIK	“up-regulates activity”	GSN	phosphorylation
CASP3	down-regulates	GSN	cleavage
SRC	up-regulates	GSN	phosphorylation
SRC	unknown	GSN	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 178 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	5	17.0×	3e-03
RHOQ GTPase cycle	6	8.4×	8e-03
Cellular response to chemical stress	7	7.8×	4e-03
Clathrin-mediated endocytosis	9	6.0×	3e-03
PIP3 activates AKT signaling	11	5.7×	1e-03
RAC1 GTPase cycle	10	4.7×	6e-03
Cellular responses to stress	15	4.3×	1e-03
Cellular responses to stimuli	15	3.7×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of DNA replication	5	17.7×	3e-03
positive regulation of miRNA transcription	8	14.2×	1e-04
chromatin remodeling	11	4.9×	5e-03
negative regulation of apoptotic process	18	3.8×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

990 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	509
Likely benign	297
Benign	53

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1457452	NM_198252.3(GSN):c.480C>A (p.Asn160Lys)	Pathogenic
1722763	NM_198252.3(GSN):c.1267T>C (p.Tyr423His)	Pathogenic
3374701	NM_198252.3(GSN):c.749A>G (p.Tyr250Cys)	Pathogenic
2446395	NM_198252.3(GSN):c.-9-1987dup	Likely pathogenic

SpliceAI

3837 predictions. Top by Δscore:

Variant	Effect	Δscore
9:121209363:GAC:G	donor_gain	1.0000
9:121209371:A:T	donor_gain	1.0000
9:121209394:CATGG:C	donor_loss	1.0000
9:121209395:ATGGT:A	donor_loss	1.0000
9:121209396:TGGTG:T	donor_loss	1.0000
9:121209398:G:GA	donor_loss	1.0000
9:121209399:T:G	donor_loss	1.0000
9:121231239:TGG:T	donor_gain	1.0000
9:121231240:GGAAG:G	donor_gain	1.0000
9:121281469:GGTA:G	acceptor_gain	1.0000
9:121302125:C:G	donor_gain	1.0000
9:121302130:G:GT	donor_gain	1.0000
9:121302131:A:T	donor_gain	1.0000
9:121302142:GCA:G	donor_gain	1.0000
9:121302145:G:GG	donor_gain	1.0000
9:121302163:GC:G	donor_gain	1.0000
9:121302163:GCTGG:G	donor_gain	1.0000
9:121302166:GG:G	donor_gain	1.0000
9:121302167:GG:G	donor_gain	1.0000
9:121302907:GTA:G	acceptor_loss	1.0000
9:121302909:A:AG	acceptor_gain	1.0000
9:121302910:G:A	acceptor_loss	1.0000
9:121302910:G:GC	acceptor_gain	1.0000
9:121302910:GGC:G	acceptor_gain	1.0000
9:121302910:GGCA:G	acceptor_gain	1.0000
9:121302910:GGCAA:G	acceptor_gain	1.0000
9:121303056:G:GT	donor_gain	1.0000
9:121303061:ACAAG:A	donor_loss	1.0000
9:121303065:GGT:G	donor_loss	1.0000
9:121303066:G:A	donor_loss	1.0000

AlphaMissense

1685 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:121302029:T:A	W71R	0.999
9:121302029:T:C	W71R	0.999
9:121302161:T:A	W115R	0.999
9:121302161:T:C	W115R	0.999
9:121302167:G:C	G117R	0.999
9:121302911:G:T	G117V	0.999
9:121310825:T:C	F216L	0.999
9:121310827:C:A	F216L	0.999
9:121310827:C:G	F216L	0.999
9:121312351:T:A	W227R	0.999
9:121312351:T:C	W227R	0.999
9:121302033:G:C	R72P	0.998
9:121302098:G:C	A94P	0.998
9:121302111:T:C	L98P	0.998
9:121302153:T:C	L112P	0.998
9:121302163:G:C	W115C	0.998
9:121302163:G:T	W115C	0.998
9:121302167:G:T	G117C	0.998
9:121302911:G:A	G117D	0.998
9:121302921:C:G	C120W	0.998
9:121302928:G:C	D123H	0.998
9:121302944:C:A	A128D	0.998
9:121302965:T:C	L135P	0.998
9:121303001:G:C	R147P	0.998
9:121312390:G:C	A240P	0.998
9:121312415:G:C	R248P	0.998
9:121302031:G:C	W71C	0.997
9:121302031:G:T	W71C	0.997
9:121302105:T:A	V96D	0.997
9:121302947:C:A	A129D	0.997

dbSNP variants (sampled 300 via entrez): RS1000012556 (9:121241576 T>C), RS1000058860 (9:121305506 A>C), RS1000083470 (9:121221719 G>A,T), RS1000091937 (9:121261889 C>A,G), RS1000118765 (9:121320954 G>C), RS1000156170 (9:121249235 G>T), RS1000162310 (9:121268136 A>G,T), RS1000173248 (9:121217750 T>A), RS1000228153 (9:121212283 G>A), RS1000234743 (9:121309586 A>G), RS1000276808 (9:121299391 C>T), RS1000285495 (9:121255203 C>T), RS1000288426 (9:121286657 G>A), RS1000307788 (9:121299113 C>T), RS1000315341 (9:121268700 G>A)

Disease associations

OMIM: gene MIM:137350 | disease phenotypes: MIM:105120

GenCC curated gene-disease

Disease	Classification	Inheritance
Finnish type amyloidosis	Definitive	Autosomal recessive

Mondo (1): Finnish type amyloidosis (MONDO:0007097)

Orphanet (1): AGel amyloidosis (Orphanet:85448)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000100	Nephrotic syndrome
HP:0000217	Xerostomia
HP:0000365	Hearing impairment
HP:0000478	Abnormality of the eye
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000597	Ophthalmoparesis
HP:0000707	Abnormality of the nervous system
HP:0000716	Depression
HP:0000763	Sensory neuropathy
HP:0000958	Dry skin
HP:0000969	Edema
HP:0000973	Cutis laxa
HP:0000978	Bruising susceptibility
HP:0000989	Pruritus
HP:0001005	Dermatological manifestations of systemic disorders
HP:0001097	Keratoconjunctivitis sicca
HP:0001138	Optic neuropathy
HP:0001149	Lattice corneal dystrophy
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001271	Polyneuropathy
HP:0001278	Orthostatic hypotension
HP:0001283	Bulbar palsy
HP:0001488	Bilateral ptosis
HP:0001638	Cardiomyopathy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_2844	Blood protein levels	5.000000e-09

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537459	Meretoja syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295700 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

115 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	7
bisphenol A	affects expression, affects cotreatment, decreases methylation, decreases expression, increases activity (+4 more)	6
trichostatin A	affects cotreatment, increases expression, affects expression	4
Cadmium	increases abundance, increases palmitoylation, increases expression, decreases expression, affects binding (+1 more)	4
Cyclosporine	decreases expression	4
Aflatoxin B1	affects expression, increases expression	4
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, decreases expression, increases expression	4
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
Rosiglitazone	affects expression, increases expression	3
Estradiol	affects expression, affects binding, decreases reaction, decreases expression, increases activity	3
Tetrachlorodibenzodioxin	increases expression	3
Tretinoin	increases expression	3
methylmercuric chloride	decreases expression	2
bisphenol AF	increases expression, affects binding, affects folding, decreases reaction	2
Troglitazone	decreases expression, increases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, increases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Hydrogen Peroxide	affects expression, increases expression	2
Mercury	affects expression, decreases expression	2
Nickel	affects binding, decreases expression	2
Smoke	decreases reaction, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Vitamin K 3	affects response to substance	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
methylselenic acid	increases expression	1
VX-agent	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4119008	Binding	Binding affinity to GSN in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4PA	U2OS GSN KO	Cancer cell line	Female
CVCL_B9VK	Abcam HeLa GSN KO	Cancer cell line	Female
CVCL_D1T4	Abcam U-87MG GSN KO	Cancer cell line	Male
CVCL_SQ68	HAP1 GSN (-) 1	Cancer cell line	Male
CVCL_XP42	HAP1 GSN (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.