FLII

Summary

FLII (FLII actin remodeling protein, HGNC:3750) is a protein-coding gene on chromosome 17p11.2, encoding Protein flightless-1 homolog (Q13045). Is a regulator of actin polymerization, required for proper myofibril organization and regulation of the length of sarcomeric thin filaments.

This gene encodes a protein with a gelsolin-like actin binding domain and an N-terminal leucine-rich repeat-protein protein interaction domain. The protein is similar to a Drosophila protein involved in early embryogenesis and the structural organization of indirect flight muscle. The gene is located within the Smith-Magenis syndrome region on chromosome 17.

Source: NCBI Gene 2314 — RefSeq curated summary.

At a glance

• Gene–disease (curated): bleeding disorder, platelet-type, 21 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 38
• Clinical variants (ClinVar): 602 total — 7 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_002018

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3750
Approved symbol	FLII
Name	FLII actin remodeling protein
Location	17p11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLI, FLIL, Fli1, MGC39265
Ensembl gene	ENSG00000177731
Ensembl biotype	protein_coding
OMIM	600362
Entrez	2314

Gene structure

Transcript identifiers

Ensembl transcripts: 64 — 44 protein_coding, 15 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000327031, ENST00000459958, ENST00000461110, ENST00000465046, ENST00000473425, ENST00000474265, ENST00000478416, ENST00000487369, ENST00000487693, ENST00000488221, ENST00000488932, ENST00000493401, ENST00000493600, ENST00000496727, ENST00000545457, ENST00000577398, ENST00000577402, ENST00000577485, ENST00000577626, ENST00000578101, ENST00000578558, ENST00000579294, ENST00000580453, ENST00000580966, ENST00000581349, ENST00000581401, ENST00000581858, ENST00000582626, ENST00000584444, ENST00000628188, ENST00000855804, ENST00000855805, ENST00000855806, ENST00000855807, ENST00000855808, ENST00000855809, ENST00000855810, ENST00000855811, ENST00000855812, ENST00000855813, ENST00000855814, ENST00000855815, ENST00000855816, ENST00000938403, ENST00000938404, ENST00000938405, ENST00000938406, ENST00000938407, ENST00000938408, ENST00000938409, ENST00000938410, ENST00000960098, ENST00000960099, ENST00000960100, ENST00000960101, ENST00000960102, ENST00000960103, ENST00000960104, ENST00000960105, ENST00000960107, ENST00000960112, ENST00000960115, ENST00000960116, ENST00000960118

RefSeq mRNA: 3 — MANE Select: NM_002018 NM_001256264, NM_001256265, NM_002018

CCDS: CCDS11192, CCDS58521, CCDS58522

Canonical transcript exons

ENST00000327031 — 30 exons

Exon	Start	End
ENSE00002720164	18258628	18258738
ENSE00003461773	18254769	18254854
ENSE00003469527	18254521	18254682
ENSE00003476774	18246913	18247052
ENSE00003477019	18245934	18246062
ENSE00003477715	18244815	18245272
ENSE00003507178	18247929	18248033
ENSE00003520276	18254079	18254182
ENSE00003543463	18256909	18257019
ENSE00003554109	18245354	18245419
ENSE00003561181	18245744	18245850
ENSE00003568805	18250838	18251017
ENSE00003572991	18248550	18248721
ENSE00003577313	18249127	18249201
ENSE00003586006	18247657	18247848
ENSE00003597318	18255183	18255263
ENSE00003600977	18247169	18247357
ENSE00003602139	18251680	18251816
ENSE00003606371	18248800	18248883
ENSE00003636402	18252472	18252556
ENSE00003645176	18251265	18251477
ENSE00003651192	18253301	18253458
ENSE00003659270	18251999	18252146
ENSE00003666198	18249326	18249408
ENSE00003669553	18246594	18246828
ENSE00003670967	18253544	18253719
ENSE00003678696	18256526	18256597
ENSE00003679645	18245555	18245660
ENSE00003687926	18246162	18246222
ENSE00003688582	18246308	18246462

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.9999 / max 301.4024, expressed in 1821 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164819	59.5184	1820
164816	0.6036	361
164815	0.4017	201
164820	0.3741	193
164818	0.0616	25
164817	0.0404	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.32	gold quality
apex of heart	UBERON:0002098	99.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.16	gold quality
gastrocnemius	UBERON:0001388	99.08	gold quality
skeletal muscle tissue	UBERON:0001134	99.04	gold quality
metanephros cortex	UBERON:0010533	99.02	gold quality
spleen	UBERON:0002106	99.01	gold quality
mucosa of transverse colon	UBERON:0004991	98.99	gold quality
pituitary gland	UBERON:0000007	98.95	gold quality
lower esophagus	UBERON:0013473	98.92	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.92	gold quality
adenohypophysis	UBERON:0002196	98.90	gold quality
muscle of leg	UBERON:0001383	98.89	gold quality
minor salivary gland	UBERON:0001830	98.82	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.81	gold quality
right lobe of thyroid gland	UBERON:0001119	98.80	gold quality
granulocyte	CL:0000094	98.79	gold quality
left testis	UBERON:0004533	98.79	gold quality
esophagus	UBERON:0001043	98.76	gold quality
right testis	UBERON:0004534	98.74	gold quality
left lobe of thyroid gland	UBERON:0001120	98.73	gold quality
endocervix	UBERON:0000458	98.72	gold quality
upper lobe of left lung	UBERON:0008952	98.71	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.71	gold quality
saliva-secreting gland	UBERON:0001044	98.70	gold quality
body of pancreas	UBERON:0001150	98.70	gold quality
heart left ventricle	UBERON:0002084	98.69	gold quality
fundus of stomach	UBERON:0001160	98.67	gold quality
prostate gland	UBERON:0002367	98.66	gold quality
esophagus mucosa	UBERON:0002469	98.66	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.76

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FLI1	Activation

Upstream regulators (CollecTRI, top): ESR1, NCOA1, NCOA2, NCOA3, SPI1, ZNF699

miRNA regulators (miRDB)

17 targeting FLII, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-3622A-3P	97.06	66.43	1000
HSA-MIR-6729-3P	96.91	66.79	703
HSA-MIR-3622B-3P	96.82	66.36	988

Literature-anchored findings (GeneRIF, showing 32)

• performs an essential function in early embryonic development (PMID:11971982)
• These data suggest that Flightless-I may facilitate interaction of the p160 coactivator complex with other coactivators or coactivator complexes containing actin or actin-like proteins. (PMID:14966289)
• effect of FliI protein on actin remodelling is a vital part of cellular motility, contraction and adhesion. Exact signaling pathways and mechanisms underpinning FliI effects in wound healing are yet to be fully identified[review] (PMID:17526423)
• These findings support a novel mechanism whereby cytosolic CaMK-II influences beta-catenin dependent gene expression through Fli-I. (PMID:18588881)
• The interactions between MyD88 and multiple positive and negative regulators LRRFIP2, FLAP-1, and Fliih are highly dynamic and time-course dependent in differentially regulating/modulating NF-kappa B signal transduction. (PMID:19265123)
• These findings support the model that CISK phosphorylates FLII and activates nuclear receptor transcription and suggest a new cell survival signaling pathway mediated by PI 3-kinase and CISK. (PMID:19293151)
• Recruitment of the SWI/SNF chromatin remodeling complex to steroid hormone-regulated promoters by nuclear receptor coactivator flightless-I. (PMID:19720835)
• Fli-I promotes the GTP-bound active Rho-mediated relief of the autoinhibition of Daam1 and mDia1. Thus, Fli-I is a novel positive regulator of Rho-induced linear actin assembly mediated by DRFs. (PMID:20223827)
• Flii is constitutively secreted from macrophages and fibroblasts and is present in human plasma. (PMID:22718342)
• FLII is a component of the ChREBP transcriptional complex and negatively regulates ChREBP function in cancer cells. (PMID:24055811)
• Demonstrate an important role for Flii in the development and regulation of the epidermal barrier, which may contribute to the impaired healing and skin fragility of epidermolysis bullosa patients. (PMID:24375017)
• These data suggest FLII as a key regulator of ERalpha-mediated transcription through its role in regulating chromatin accessibility for the binding of RNA Polymerase II and possibly other transcriptional coactivators. (PMID:24632205)
• Flightless-I (Drosophila) homolog (FLII) activates TGFbeta1-mediated expression of COL1A2 gene. (PMID:25451260)
• Studies suggest that Flii enhances cutaneous squamous cell carcinoma progression by decreasing apoptosis and enhancing tumor cell invasion. (PMID:26497552)
• FLII plays a tumor-suppressive role and serves as a crucial determinant of resistance of prostate cancer to endocrine therapies. (PMID:26527749)
• Data show that the ability of Ca(2+) to accentuate the activity of NLRP3 inflammasome is abrogated in Flightless-I (FliI) and leucine-rich repeat FliI-interaction protein 2 (LRRFIP2)-knockdown macrophages. (PMID:27431477)
• FLII is associated with SENP3 and the MLL1/2 complex and FLII is indispensible for H3K4 methylation and proper loading of active RNA polymerase II at this gene locus. (PMID:28344658)
• Low FLII expression is associated with lung carcinoma. (PMID:28498392)
• Together, the data demonstrate the critical requirement of GGAA-microsatellites as EWS/FLI activating response elements in vivo and reveal an unexpected role for the EWS portion of the EWS/FLI fusion in binding to sweet-spot GGAA-microsatellites. (PMID:28847958)
• Flightless-I functions as a checkpoint protein for selective autophagy by interacting with p62 to block its recognition of LC3, leading to tumorigenesis in breast cancer. (PMID:29898994)
• this study shows that Flii alters the inflammatory response and autoantibody profile in an OVA-induced atopic dermatitis skin-like disease (PMID:30147695)
• Data reveal an unknown mechanism by which the transcription coactivator FLII regulates the GR-mediated repression of ERalpha target gene expression in MCF-7 cells. (PMID:30369516)
• the role of Flii in ulcerative colitis and mucosal damage (PMID:31488864)
• Flightless I, a contributing factor to skin blistering in Kindler syndrome patients? (PMID:31614010)
• Flightless-1 inhibits ER stress-induced apoptosis in colorectal cancer cells by regulating Ca(2+) homeostasis. (PMID:32504039)
• Role of the small GTPase activating protein IQGAP1 in collagen phagocytosis. (PMID:32643295)
• Attenuation of Flightless I Increases Human Pericyte Proliferation, Migration and Angiogenic Functions and Improves Healing in Murine Diabetic Wounds. (PMID:32764293)
• Increasing the level of cytoskeletal protein Flightless I reduces adhesion formation in a murine digital flexor tendon model. (PMID:32854733)
• Flightless I Homolog Reverses Enzalutamide Resistance through PD-L1-Mediated Immune Evasion in Prostate Cancer. (PMID:34011528)
• FLII and MLL1 Cooperatively Regulate Aryl Hydrocarbon Receptor-Mediated Transcription in ARPE-19 Cells. (PMID:34698116)
• Increased Expression of Flightless I in Cutaneous Squamous Cell Carcinoma Affects Wnt/beta-Catenin Signaling Pathway. (PMID:34948000)
• A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy. (PMID:37126682)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	flii	ENSDARG00000059701
mus_musculus	Flii	ENSMUSG00000002812
rattus_norvegicus	Flii	ENSRNOG00000004159
drosophila_melanogaster	fliI	FBGN0000709
caenorhabditis_elegans		WBGENE00001443

Paralogs (7): SCIN (ENSG00000006747), CAPG (ENSG00000042493), VIL1 (ENSG00000127831), AVIL (ENSG00000135407), VILL (ENSG00000136059), GSN (ENSG00000148180), SVIL (ENSG00000197321)

Protein

Protein identifiers

Protein flightless-1 homolog — Q13045 (reviewed: Q13045)

All UniProt accessions (11): Q13045, J3KS39, J3KS54, J3KT47, J3QLR6, J3QQQ2, J3QQU5, K7EJJ7, K7EP27, K7EP37, K7EQZ7

UniProt curated annotations — full annotation on UniProt →

Function. Is a regulator of actin polymerization, required for proper myofibril organization and regulation of the length of sarcomeric thin filaments. It also plays a role in the assembly of cardiomyocyte cell adhesion complexes. Regulates cytoskeletal rearrangements involved in cytokinesis and cell migration, by inhibiting Rac1-dependent paxillin phosphorylation. May play a role as coactivator in transcriptional activation by hormone-activated nuclear receptors (NR) and acts in cooperation with NCOA2 and CARM1. Involved in estrogen hormone signaling.

Subunit / interactions. Interacts with actin, ACTL6A, NCOA2 and CARM1. Interacts with LRRFIP1, LRRFIP2 and MYD88. Upon LPS stimulation, LRRFIP2 competes for MYD88-binding. LRRFIP1 constitutively blocks the interaction with MyD88, even in the absence of LPS. Interacts with the nuclear receptors ESR1 and THRB. Interacts with SGK3. Interacts (via the gelsolin-like region) with TMOD1. Interacts with (via the gelsolin-like region) TMOD3. Interacts with LMOD2, VCL, GSN and DES.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Cell projection. Podosome. Cell junction. Focal adhesion.

Tissue specificity. Strongest expression in skeletal muscle with high expression also in the heart and lung.

Disease relevance. Cardiomyopathy, dilated, 2J (CMD2J) [MIM:620635] A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2J is an autosomal recessive form characterized by onset of heart failure within the first year of life. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13045-1	1	yes
Q13045-2	2
Q13045-3	3

RefSeq proteins (3): NP_001243193, NP_001243194, NP_002009* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR007122	Villin/Gelsolin	Family
IPR007123	Gelsolin-like_dom	Domain
IPR029006	ADF-H/Gelsolin-like_dom_sf	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR055414	LRR_R13L4/SHOC2-like	Domain

Pfam: PF00560, PF00626, PF13855, PF23598

UniProt features (48 total): repeat 21, modified residue 7, sequence variant 5, region of interest 4, compositionally biased region 3, splice variant 3, mutagenesis site 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13045-F1	81.20	0.41

Functional residue map

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

Post-translational modifications (7): 1, 21, 406, 436, 818, 856, 860

Mutagenesis-validated functional residues (2):

Position	Phenotype
586	no change in esr1 binding but reduced binding to actl6a and reduced coactivator function.
603	no change in binding to actl6a or in coactivator function.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 821 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, FXR_IR1_Q6, MYAATNNNNNNNGGC_UNKNOWN, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, WALLACE_PROSTATE_CANCER_RACE_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_MYELOID_CELL_DEVELOPMENT, RORA1_01, LFA1_Q6, HOFMANN_CELL_LYMPHOMA_UP, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_BARBED_END_ACTIN_FILAMENT_CAPPING, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (5): actin polymerization or depolymerization (GO:0008154), myofibril assembly (GO:0030239), sarcomere organization (GO:0045214), actin filament severing (GO:0051014), barbed-end actin filament capping (GO:0051016)

GO Molecular Function (4): actin binding (GO:0003779), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), actin filament binding (GO:0051015), protein binding (GO:0005515)

GO Cellular Component (13): podosome (GO:0002102), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), brush border (GO:0005903), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), centriolar satellite (GO:0034451), centrosome (GO:0005813), cytoskeleton (GO:0005856), cell projection (GO:0042995), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
actomyosin structure organization	2
actin filament organization	1
cellular component assembly involved in morphogenesis	1
striated muscle cell development	1
supramolecular fiber organization	1
membraneless organelle assembly	1
myofibril assembly	1
actin filament-based process	1
actin filament capping	1
cytoskeletal protein binding	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
actin binding	1
protein-containing complex binding	1
binding	1
actin-based cell projection	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
microvillus	1
apical part of cell	1
cluster of actin-based cell projections	1
cell-substrate junction	1
cytoskeleton	1
centrosome	1
centriole	1
microtubule organizing center	1
intracellular membraneless organelle	1
cell junction	1

Protein interactions and networks

STRING

1810 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FLII	LRRFIP1	Q32MZ4	982
FLII	LRRFIP2	Q9Y608	939
FLII	EWSR1	Q01844	896
FLII	LLGL1	Q15334	836
FLII	GCFC2	P16383	763
FLII	DHX9	Q08211	722
FLII	MYD88	P78397	712
FLII	PARP1	P09874	577
FLII	UACA	Q9BZF9	576
FLII	ACTL6A	O96019	568
FLII	RBM8A	Q9Y5S9	564
FLII	SNRPC	P09234	541
FLII	EP300	Q09472	541
FLII	IGFBP3	P17936	540
FLII	MYH9	P35579	531

IntAct

154 interactions, top by confidence:

A	B	Type	Score
NPHP1	NPHP4	psi-mi:“MI:2364”(proximity)	0.930
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
FLII	LRRFIP1	psi-mi:“MI:0915”(physical association)	0.690
LRRFIP1	FLII	psi-mi:“MI:0407”(direct interaction)	0.690
HSP90AA1	CHUK	psi-mi:“MI:0914”(association)	0.670
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
FLII	TMOD1	psi-mi:“MI:0914”(association)	0.640
DCAF7	PFDN6	psi-mi:“MI:0914”(association)	0.570
LRRFIP2	FLII	psi-mi:“MI:0915”(physical association)	0.550
HSP90AA1	USP19	psi-mi:“MI:0914”(association)	0.530
ZNRD2	MYO9A	psi-mi:“MI:0914”(association)	0.530
FBXO40	MYO1D	psi-mi:“MI:0914”(association)	0.530
TMOD1	GSN	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
FLII	MATR3	psi-mi:“MI:0915”(physical association)	0.400
FLII	AKAP8	psi-mi:“MI:0915”(physical association)	0.400
Ppp1cb	MYO1C	psi-mi:“MI:0914”(association)	0.350
MYH9	PLEKHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (400): FLII (Affinity Capture-MS), FLII (Affinity Capture-MS), FLII (Reconstituted Complex), FLII (Phenotypic Suppression), FLII (Phenotypic Suppression), FLII (Affinity Capture-MS), FLII (Affinity Capture-MS), FLII (Co-fractionation), FLII (Affinity Capture-MS), FLII (Affinity Capture-MS), FLII (Affinity Capture-MS), FLII (Affinity Capture-MS), FLII (Affinity Capture-MS), FLII (Proximity Label-MS), FLII (Proximity Label-MS)

ESM2 similar proteins: A0A7J6K9S4, A1YVX4, A2WYE9, A4HVU6, A8JAM0, B9EHT4, C8VBH4, F1M4A4, F4HX15, F8WK50, O46072, P0C5E7, P34268, P34305, P53621, P53904, P84737, Q09299, Q0J3D9, Q0JGK4, Q13045, Q24020, Q27954, Q2UMQ5, Q3V0G7, Q4IEV4, Q4P3S3, Q4WHG1, Q57WH1, Q5R686, Q61T02, Q6C710, Q6P5D3, Q6P7W2, Q755D2, Q76L34, Q8CIE6, Q8CIG3, Q8IY37, Q8S9F2

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

2 interactions.

A	Effect	B	Mechanism
SGK3	up-regulates	FLII	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 163 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
Striated Muscle Contraction	6	18.3×	3e-04
Sensory processing of sound	6	18.3×	3e-04
Signaling by ALK in cancer	5	13.5×	2e-03
Smooth Muscle Contraction	5	13.2×	2e-03
Regulation of actin dynamics for phagocytic cup formation	6	10.9×	1e-03
Signaling by ALK fusions and activated point mutants	7	10.4×	6e-04
Sensory processing of sound by outer hair cells of the cochlea	5	10.1×	7e-03
Sensory processing of sound by inner hair cells of the cochlea	6	9.7×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to reactive oxygen species	5	15.3×	3e-03
platelet aggregation	6	15.1×	1e-03
actin filament organization	13	11.5×	1e-07
muscle contraction	6	9.3×	5e-03
endocytosis	8	5.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	7
Uncertain significance	330
Likely benign	136
Benign	52

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1333008	Single allele	Pathogenic
1703851	NM_002017.5(FLI1):c.844C>T (p.Gln282Ter)	Pathogenic
217031	NM_002017.5(FLI1):c.970C>T (p.Arg324Trp)	Pathogenic
2663896	NM_002018.4(FLII):c.1360C>T (p.Gln454Ter)	Pathogenic
2663897	NM_002018.4(FLII):c.3502C>T (p.Arg1168Trp)	Pathogenic
424636	NM_002017.5(FLI1):c.1033A>G (p.Lys345Glu)	Pathogenic
4541671	NM_002017.5(FLI1):c.338dup (p.Pro114fs)	Pathogenic
1684367	NM_002017.5(FLI1):c.946G>T (p.Glu316Ter)	Likely pathogenic
1684421	NM_002017.5(FLI1):c.1019G>C (p.Arg340Pro)	Likely pathogenic
1699194	NM_002018.4(FLII):c.3718C>T (p.Arg1240Cys)	Likely pathogenic
424632	NM_002017.5(FLI1):c.1009C>T (p.Arg337Trp)	Likely pathogenic
4541672	NM_002017.5(FLI1):c.969_973del (p.Arg324fs)	Likely pathogenic
4849343	NM_002018.4(FLII):c.1382_1383+1del	Likely pathogenic
627497	Single allele	Likely pathogenic

SpliceAI

3930 predictions. Top by Δscore:

Variant	Effect	Δscore
17:18245270:TACC:T	acceptor_loss	1.0000
17:18245271:ACC:A	acceptor_loss	1.0000
17:18245520:T:TA	donor_gain	1.0000
17:18245552:CACCT:C	donor_gain	1.0000
17:18245554:CCT:C	donor_gain	1.0000
17:18245556:T:TA	donor_gain	1.0000
17:18245928:CCTGA:C	donor_loss	1.0000
17:18245929:CTGAC:C	donor_loss	1.0000
17:18245930:TGA:T	donor_loss	1.0000
17:18245931:GACCT:G	donor_loss	1.0000
17:18245932:A:C	donor_loss	1.0000
17:18245933:CCTG:C	donor_gain	1.0000
17:18246059:GAACC:G	acceptor_loss	1.0000
17:18246157:CCCA:C	donor_loss	1.0000
17:18246159:CAC:C	donor_loss	1.0000
17:18246160:ACCT:A	donor_loss	1.0000
17:18246325:G:GA	donor_gain	1.0000
17:18246339:T:C	donor_gain	1.0000
17:18246378:T:TA	donor_gain	1.0000
17:18246595:T:TA	donor_gain	1.0000
17:18246602:T:TA	donor_gain	1.0000
17:18246623:A:AC	donor_gain	1.0000
17:18246624:C:CC	donor_gain	1.0000
17:18246624:CTT:C	donor_gain	1.0000
17:18246626:T:TA	donor_gain	1.0000
17:18246712:T:TA	donor_gain	1.0000
17:18246824:AGTAC:A	acceptor_gain	1.0000
17:18246825:GTAC:G	acceptor_gain	1.0000
17:18246826:TAC:T	acceptor_gain	1.0000
17:18246826:TACC:T	acceptor_loss	1.0000

AlphaMissense

8375 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:18245410:A:G	W1207R	1.000
17:18245410:A:T	W1207R	1.000
17:18246020:A:G	W1104R	1.000
17:18246020:A:T	W1104R	1.000
17:18246166:A:G	L1088P	1.000
17:18246652:A:G	L998P	1.000
17:18246686:A:G	W987R	1.000
17:18246686:A:T	W987R	1.000
17:18246919:A:G	L937P	1.000
17:18247018:A:G	L904P	1.000
17:18254629:A:G	L156P	1.000
17:18254771:G:C	N137K	1.000
17:18254771:G:T	N137K	1.000
17:18254787:A:G	L132P	1.000
17:18254840:G:C	N114K	1.000
17:18254840:G:T	N114K	1.000
17:18255243:G:C	N89K	1.000
17:18255243:G:T	N89K	1.000
17:18255253:G:T	A86D	1.000
17:18256574:G:C	N66K	1.000
17:18256574:G:T	N66K	1.000
17:18256970:A:G	L38P	1.000
17:18245369:G:C	S1220R	0.999
17:18245369:G:T	S1220R	0.999
17:18245371:T:G	S1220R	0.999
17:18245373:A:G	L1219P	0.999
17:18245403:C:T	G1209E	0.999
17:18245404:C:A	G1209W	0.999
17:18245408:C:A	W1207C	0.999
17:18245408:C:G	W1207C	0.999

dbSNP variants (sampled 300 via entrez): RS1000243591 (17:18251327 C>G,T), RS1000278019 (17:18257629 C>A,T), RS1000330961 (17:18257366 C>G), RS1000493434 (17:18257425 T>G), RS1000537794 (17:18246515 G>A), RS1000669361 (17:18256008 G>A,C), RS1000845436 (17:18252852 T>C), RS1000870724 (17:18259207 G>A), RS1000950971 (17:18247579 G>A,C), RS1001207408 (17:18256289 G>C), RS1001211240 (17:18250906 T>C), RS1001820523 (17:18251892 C>A,T), RS1001998606 (17:18261012 G>C), RS1002187821 (17:18252244 G>C,T), RS1002301065 (17:18248245 A>G)

Disease associations

OMIM: gene MIM:600362 | disease phenotypes: MIM:617443, MIM:135150, MIM:620635, MIM:154700, MIM:147791

GenCC curated gene-disease

Disease	Classification	Inheritance
bleeding disorder, platelet-type, 21	Strong	Autosomal dominant
cardiomyopathy, dilated, 2j	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
cardiomyopathy, dilated, 2j	Moderate	AR
bleeding disorder, platelet-type, 21	Moderate	AD

Mondo (7): bleeding disorder, platelet-type, 21 (MONDO:0054577), Birt-Hogg-Dube syndrome (MONDO:0800444), dilated cardiomyopathy (MONDO:0005021), cardiomyopathy, dilated, 2j (MONDO:0957984), Marfan syndrome (MONDO:0007947), thrombocytopenia (MONDO:0002049), Jacobsen syndrome (MONDO:0007838)

Orphanet (5): Birt-Hogg-Dubé syndrome (Orphanet:122), Dilated cardiomyopathy (Orphanet:217604), Marfan syndrome type 1 (Orphanet:284963), Marfan syndrome (Orphanet:558), Jacobsen syndrome (Orphanet:2308)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001635	Congestive heart failure
HP:0001644	Dilated cardiomyopathy
HP:0001684	Secundum atrial septal defect
HP:0003593	Infantile onset
HP:0012666	Severely reduced left ventricular ejection fraction

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST000817_37	Height	4.000000e-11
GCST001454_10	Rheumatoid arthritis	8.000000e-07
GCST001712_40	Myopia (pathological)	2.000000e-08
GCST002337_48	Amyotrophic lateral sclerosis (sporadic)	5.000000e-07
GCST003155_14	Systemic lupus erythematosus	1.000000e-10
GCST003156_32	Systemic lupus erythematosus	2.000000e-08
GCST003622_38	Systemic lupus erythematosus	1.000000e-06
GCST004603_99	Platelet count	5.000000e-14
GCST004607_38	Plateletcrit	1.000000e-14
GCST004719_4	Left ventricular obstructive tract defect (inherited effect)	3.000000e-06
GCST004785_33	Vitiligo	4.000000e-08
GCST005173_37	Coronary artery calcified atherosclerotic plaque (130 HU threshold) in type 2 diabetes	2.000000e-06
GCST005748_6	Digit length ratio (right hand)	4.000000e-09
GCST005749_17	Digit length ratio (left hand)	1.000000e-12
GCST005749_9	Digit length ratio (left hand)	4.000000e-13
GCST005750_7	Digit length ratio	1.000000e-11
GCST005987_50	Albumin-globulin ratio	2.000000e-11
GCST005990_15	Non-albumin protein levels	3.000000e-11
GCST006048_27	Rheumatoid arthritis (ACPA-positive)	7.000000e-10
GCST006979_236	Heel bone mineral density	8.000000e-14
GCST007157_7	Corneal astigmatism	4.000000e-07
GCST008839_458	Height	8.000000e-12
GCST010002_202	Refractive error	1.000000e-17
GCST012227_635	Hip circumference adjusted for BMI	2.000000e-12
GCST90002381_530	Eosinophil count	4.000000e-24
GCST90002382_301	Eosinophil percentage of white cells	6.000000e-24
GCST90002392_365	Mean corpuscular volume	1.000000e-09
GCST90002393_453	Monocyte count	8.000000e-14
GCST90002394_356	Monocyte percentage of white cells	7.000000e-10
GCST90002394_357	Monocyte percentage of white cells	1.000000e-11

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004207	pathological myopia
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0004723	coronary artery calcification
EFO:0004841	digit length ratio
EFO:0005128	albumin:globulin ratio measurement
EFO:0009270	heel bone mineral density
EFO:1002040	Corneal astigmatism
EFO:0008039	BMI-adjusted hip circumference
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D008382	Marfan Syndrome	C05.116.099.674; C14.240.400.725; C14.280.400.725; C16.131.077.550; C16.131.240.400.720; C16.320.540; C17.300.500
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	4
Cadmium Chloride	increases expression, decreases reaction, increases abundance, increases palmitoylation	3
bisphenol F	affects cotreatment, increases methylation, increases expression	2
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	decreases methylation, decreases expression	2
Valproic Acid	affects expression, decreases expression, increases methylation	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
beta-lapachone	increases expression	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
doxifluridine	decreases response to substance	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
beta-methylcholine	affects expression	1
K 7174	increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Capecitabine	decreases response to substance	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1S7	Abcam HeLa FLII KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT01295047	PHASE4	COMPLETED	Comparison of Medical Therapies in Marfan Syndrome.
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	PHASE3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	PHASE3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT00429364	PHASE3	COMPLETED	Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome
NCT00485368	PHASE3	COMPLETED	Angiotensin Converting Enzyme Inhibitors in Marfan Syndrome
NCT00683124	PHASE3	UNKNOWN	Nebivolol Versus Losartan Versus Nebivolol+Losartan Against Aortic Root Dilation in Genotyped Marfan Patients
NCT00723801	PHASE3	COMPLETED	Effects of Losartan Versus Atenolol on Aortic and Cardiac Muscle Stiffness in Adults With Marfan Syndrome
NCT00763893	PHASE3	TERMINATED	Study of the Efficacy of Losartan on Aortic Dilatation in Patients With Marfan Syndrome
NCT00782327	PHASE3	COMPLETED	Randomized, Double-blind Study for the Evaluation of the Effect of Losartan Versus Placebo on Aortic Root Dilatation in Patients With Marfan Syndrome Under Treatment With Beta-blockers
NCT01145612	PHASE3	UNKNOWN	Atenolol Versus Losartan in the Prevention of Progressive Dilation of the Aorta in Marfan Syndrome
NCT01361087	PHASE3	WITHDRAWN	Circulating Transforming Growth Factor Beta (TGF-β) in Individuals With Marfan Syndrome
NCT01715207	PHASE3	COMPLETED	Comparison of Aliskiren vs Negative Controls on Aortic Stiffness in Patients With MFS