XIRP1

Summary

XIRP1 (xin actin binding repeat containing 1, HGNC:14301) is a protein-coding gene on chromosome 3p22.2, encoding Xin actin-binding repeat-containing protein 1 (Q702N8). Protects actin filaments from depolymerization.

The protein encoded by this gene is a striated muscle protein and belongs to the Xin actin-binding repeat-containing protein (XIRP) family. The protein functions to protect actin filaments during depolymerization. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 165904 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 408 total
• MANE Select transcript: NM_194293

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14301
Approved symbol	XIRP1
Name	xin actin binding repeat containing 1
Location	3p22.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp451D042, Xin
Ensembl gene	ENSG00000168334
Ensembl biotype	protein_coding
OMIM	609777
Entrez	165904

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000340369, ENST00000396251, ENST00000421646, ENST00000884469, ENST00000958139

RefSeq mRNA: 3 — MANE Select: NM_194293 NM_001198621, NM_001351377, NM_194293

CCDS: CCDS2683, CCDS56245, CCDS87065

Canonical transcript exons

ENST00000340369 — 2 exons

Exon	Start	End
ENSE00001410194	39183215	39189525
ENSE00001607132	39192446	39192595

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 99.65.

FANTOM5 (CAGE): breadth broad, TPM avg 6.3524 / max 1738.2289, expressed in 238 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41744	6.2605	235
41745	0.0472	11
41741	0.0270	12
41743	0.0128	6
41742	0.0050	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	99.65	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.41	gold quality
tibialis anterior	UBERON:0001385	99.39	gold quality
apex of heart	UBERON:0002098	99.37	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.20	gold quality
myocardium	UBERON:0002349	99.05	gold quality
heart right ventricle	UBERON:0002080	98.98	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.95	gold quality
cardiac ventricle	UBERON:0002082	98.42	gold quality
heart left ventricle	UBERON:0002084	98.42	gold quality
cardiac atrium	UBERON:0002081	98.17	gold quality
right atrium auricular region	UBERON:0006631	98.15	gold quality
quadriceps femoris	UBERON:0001377	98.09	gold quality
vastus lateralis	UBERON:0001379	97.91	gold quality
skeletal muscle tissue	UBERON:0001134	97.89	gold quality
gastrocnemius	UBERON:0001388	97.61	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.35	gold quality
deltoid	UBERON:0001476	97.30	gold quality
biceps brachii	UBERON:0001507	97.09	gold quality
muscle of leg	UBERON:0001383	95.54	gold quality
body of tongue	UBERON:0011876	95.36	gold quality
muscle tissue	UBERON:0002385	93.48	gold quality
vena cava	UBERON:0004087	92.93	gold quality
heart	UBERON:0000948	92.80	gold quality
tongue	UBERON:0001723	90.56	gold quality
superior surface of tongue	UBERON:0007371	82.35	gold quality
pharyngeal mucosa	UBERON:0000355	79.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.32	gold quality
cartilage tissue	UBERON:0002418	73.44	gold quality
pancreatic ductal cell	CL:0002079	71.41	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.84

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting XIRP1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-6815-3P	99.13	68.98	1530

Literature-anchored findings (GeneRIF, showing 10)

• Xin and XIRP2 define a novel actin-binding motif (PMID:15454575)
• Here, we identify Xin, the protein encoded by the human gene ‘cardiomyopathy associated 1’(CMYA1) as filamin c binding partner at these specialized structures where the ends of myofibrils are attached to the sarcolemma (PMID:16631741)
• Data show that in myofibrillar myopathies Xin protein exhibites significant alterations in their localization. (PMID:19151983)
• Data provide further support that ALS2CL, EPHA3, and CMYA1 are bona-fide tumor-suppressor genes and contribute to the tumorigenesis of HNSCC. (PMID:20657180)
• We identify the SH3 domains of nebulin and nebulette as novel ligands of proline-rich regions of Xin and XIRP2. (PMID:23985323)
• The strong correlation between the degree of muscle damage and Xin immunoreactivity suggests that Xin may be a suitable outcome measure to evaluate disease progression and treatment effects in clinical trials. (PMID:24225086)
• Aciculin interacts with filamin C and Xin and is essential for myofibril assembly. (PMID:24963132)
• Abnormal CMYA1 expression affects the phosphorylation of Cx43 through the protein kinase c signaling pathway, which is involved in the regulation of gap junction intercellular communication. (PMID:29176328)
• Report pathogenic XIRP1/2 rare variants in arrhythmogenic disorders such as sudden unexplained nocturnal death syndrome and Brugada syndrome. (PMID:29306897)
• An interaction of heart disease-associated proteins POPDC1/2 with XIRP1 in transverse tubules and intercalated discs. (PMID:33261556)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	xirp1	ENSDARG00000030722
mus_musculus	Xirp1	ENSMUSG00000079243
rattus_norvegicus	Xirp1	ENSRNOG00000037085

Paralogs (1): XIRP2 (ENSG00000163092)

Protein

Protein identifiers

Xin actin-binding repeat-containing protein 1 — Q702N8 (reviewed: Q702N8)

Alternative names: Cardiomyopathy-associated protein 1

All UniProt accessions (1): Q702N8

UniProt curated annotations — full annotation on UniProt →

Function. Protects actin filaments from depolymerization. Required for correct cardiac intercalated disk ultrastructure via maintenance of cell-cell adhesion stability, and as a result maintains cardiac organ morphology, conductance and heart beat rhythm. Required for development of normal skeletal muscle morphology and muscle fiber type composition. Plays a role in regulating muscle satellite cell activation and survival, as a result promotes muscle fiber recovery from injury and fatigue.

Subunit / interactions. Interacts (via N-terminus) with CTTN; the interaction promotes CTTN localization to intercalated disks in cardiomyocytes. Interacts with CTNNB1. Interacts with FLNC and VASP. Interacts with F-actin. Interacts with PGM5 (via N-terminus); the interaction competes with FLNC binding to PGM5.

Subcellular location. Cell junction. Adherens junction. Desmosome.

Tissue specificity. Expressed in skeletal muscle at areas of Z-disk disruption in a longitudinal pattern spanning one or more sarcomeres (at protein level). Expressed in the heart (at protein level). Expressed in the heart (at protein level). Expressed in the heart.

Domain organisation. Xin repeats bind F-actin.

Miscellaneous. ‘Xin’ means ‘heart’ in Chinese.

Similarity. Belongs to the Xin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q702N8-1	A	yes
Q702N8-2	B
Q702N8-3	C

RefSeq proteins (3): NP_001185550, NP_001338306, NP_919269* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012510	Actin-binding_Xin_repeat	Repeat
IPR030072	XIRP1/XIRP2	Family

Pfam: PF08043

UniProt features (71 total): repeat 17, sequence variant 14, region of interest 13, compositionally biased region 11, sequence conflict 6, modified residue 5, splice variant 3, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q702N8-F1	44.17	0.05

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 (5): 205, 208, 213, 295, 332

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 117 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, AP1_01, GOBP_REGULATION_OF_PROTEIN_BINDING, GOBP_SKELETAL_MUSCLE_TISSUE_REGENERATION, GCANCTGNY_MYOD_Q6, GOBP_GROWTH, GOBP_REGENERATION, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_BINDING, AP1_Q4_01, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_ACTIN_FILAMENT_ORGANIZATION, MODULE_301, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_MYOBLAST_DIFFERENTIATION

GO Biological Process (6): actin filament organization (GO:0007015), intracellular protein localization (GO:0008104), myoblast differentiation involved in skeletal muscle regeneration (GO:0014835), satellite cell activation involved in skeletal muscle regeneration (GO:0014901), negative regulation of protein binding (GO:0032091), actin cytoskeleton organization (GO:0030036)

GO Molecular Function (4): RNA binding (GO:0003723), actin filament binding (GO:0051015), actin binding (GO:0003779), protein binding (GO:0005515)

GO Cellular Component (6): adherens junction (GO:0005912), desmosome (GO:0030057), stress fiber (GO:0001725), focal adhesion (GO:0005925), cell junction (GO:0030054), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
skeletal muscle tissue regeneration	2
cell-cell junction	2
actin cytoskeleton organization	1
supramolecular fiber organization	1
macromolecule localization	1
myoblast differentiation	1
skeletal muscle satellite cell activation	1
protein binding	1
regulation of protein binding	1
negative regulation of binding	1
cytoskeleton organization	1
actin filament-based process	1
nucleic acid binding	1
actin binding	1
protein-containing complex binding	1
cytoskeletal protein binding	1
binding	1
actomyosin	1
contractile actin filament bundle	1
cell-substrate junction	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1426 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XIRP1	OXNAD1	Q96HP4	884
XIRP1	CAPN7	Q9Y6W3	832
XIRP1	FLNC	Q14315	659
XIRP1	CDH2	P19022	658
XIRP1	ACTN2	P35609	645
XIRP1	CAV3	P56539	611
XIRP1	PGM5	Q15124	572
XIRP1	POPDC2	Q9HBU9	558
XIRP1	TTN	Q8WZ42	544
XIRP1	NACAD	O15069	533
XIRP1	CSRP3	P50461	532
XIRP1	VASP	P50552	475
XIRP1	CASQ2	O14958	473
XIRP1	NRAP	Q86VF7	463
XIRP1	CTNNB1	P35222	452

IntAct

20 interactions, top by confidence:

A	B	Type	Score
SOCS7	NCK2	psi-mi:“MI:0914”(association)	0.670
VASP	XIRP1	psi-mi:“MI:0915”(physical association)	0.650
VASP	XIRP1	psi-mi:“MI:0407”(direct interaction)	0.650
XIRP1	VASP	psi-mi:“MI:0407”(direct interaction)	0.650
XIRP1	VASP	psi-mi:“MI:0403”(colocalization)	0.650
	XIRP1	psi-mi:“MI:0915”(physical association)	0.560
XIRP1	FLNC	psi-mi:“MI:0915”(physical association)	0.560
XIRP1	FLNC	psi-mi:“MI:0407”(direct interaction)	0.560
XIRP1	FLNC	psi-mi:“MI:0403”(colocalization)	0.560
FLNC	XIRP1	psi-mi:“MI:0915”(physical association)	0.560
XIRP1	CETN2	psi-mi:“MI:0915”(physical association)	0.400
Enah	XIRP1	psi-mi:“MI:0915”(physical association)	0.370
XIRP1	Evl	psi-mi:“MI:0915”(physical association)	0.370
SCN4A	C2CD4B	psi-mi:“MI:0914”(association)	0.350
ABCA2	ABCD4	psi-mi:“MI:0914”(association)	0.350
PTBP3		psi-mi:“MI:0914”(association)	0.350
	XIRP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (28): XIRP1 (Two-hybrid), XIRP1 (Affinity Capture-MS), XIRP1 (Affinity Capture-MS), XIRP1 (Affinity Capture-MS), XIRP1 (Affinity Capture-MS), XIRP1 (Affinity Capture-MS), CETN2 (Affinity Capture-MS), XIRP1 (Protein-peptide), XIRP1 (Affinity Capture-MS), XIRP1 (Cross-Linking-MS (XL-MS)), XIRP1 (Cross-Linking-MS (XL-MS)), XIRP1 (Protein-RNA), XIRP1 (Affinity Capture-MS), NEB (Two-hybrid), NEBL (Two-hybrid)

ESM2 similar proteins: A2AIP0, A2RRU4, A2RRW4, A4Q9F4, A6QM06, A6QNS9, A6QPC0, A8MTA8, E1BBQ2, F1LQY6, G3X6E2, H3BNL1, O70373, P29590, P50747, P55199, P97260, Q04841, Q12770, Q2TBR5, Q4QR77, Q5E9N3, Q5MNU5, Q5RDC3, Q69Z89, Q6GQT6, Q6J272, Q702N8, Q70EL4, Q7Z4S9, Q8BL74, Q8BUM9, Q8C419, Q8IVA1, Q8IW40, Q8N1F8, Q8N9H8, Q8WUA4, Q91ZP9, Q920N2

Diamond homologs: A4UGR9, O70373, Q4U4S6, Q5PZ43, Q702N8, Q71LX6, Q91957

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	315
Likely benign	43
Benign	43

Top pathogenic / likely-pathogenic (0)

SpliceAI

296 predictions. Top by Δscore:

Variant	Effect	Δscore
3:39192442:TCAC:T	donor_loss	1.0000
3:39192444:A:AC	donor_gain	1.0000
3:39192444:AC:A	donor_gain	1.0000
3:39192445:C:A	donor_loss	1.0000
3:39192445:C:CA	donor_gain	1.0000
3:39192445:CC:C	donor_gain	1.0000
3:39192445:CCA:C	donor_gain	1.0000
3:39192445:CCAA:C	donor_gain	1.0000
3:39192445:CCAAG:C	donor_gain	1.0000
3:39189445:TCCTT:T	acceptor_gain	0.9800
3:39189446:CCTTC:C	acceptor_gain	0.9800
3:39189447:CTT:C	acceptor_gain	0.9800
3:39192440:A:AC	donor_gain	0.9800
3:39192441:C:CC	donor_gain	0.9800
3:39185670:G:GC	acceptor_gain	0.9700
3:39189450:C:CC	acceptor_gain	0.9600
3:39185662:C:CC	acceptor_gain	0.9500
3:39185659:CAG:C	acceptor_gain	0.9100
3:39186122:TCC:T	donor_gain	0.9100
3:39192439:TAC:T	donor_loss	0.9100
3:39192441:CTCA:C	donor_gain	0.9100
3:39185670:G:C	acceptor_gain	0.9000
3:39185660:AG:A	acceptor_gain	0.8900
3:39185658:GCAG:G	acceptor_gain	0.8800
3:39185659:CAGC:C	acceptor_gain	0.8800
3:39192438:TTAC:T	donor_loss	0.8700
3:39185660:A:T	acceptor_gain	0.8600
3:39185657:AGCAG:A	acceptor_gain	0.8500
3:39186079:C:A	donor_gain	0.8500
3:39186163:T:A	donor_gain	0.8400

AlphaMissense

11966 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:39188635:A:G	W271R	0.996
3:39188635:A:T	W271R	0.996
3:39188628:A:G	F273S	0.995
3:39188741:G:C	F235L	0.992
3:39188741:G:T	F235L	0.992
3:39188743:A:G	F235L	0.992
3:39188742:A:G	F235S	0.991
3:39188513:A:C	F311L	0.989
3:39188513:A:T	F311L	0.989
3:39188515:A:G	F311L	0.989
3:39188627:A:C	F273L	0.989
3:39188627:A:T	F273L	0.989
3:39188629:A:G	F273L	0.989
3:39188574:A:T	I291N	0.988
3:39188631:A:G	L272P	0.987
3:39188628:A:C	F273C	0.986
3:39186718:A:C	Y910D	0.985
3:39188574:A:C	I291S	0.985
3:39188574:A:G	I291T	0.985
3:39189252:A:G	L65P	0.985
3:39187906:A:G	W514R	0.984
3:39187906:A:T	W514R	0.984
3:39188633:C:A	W271C	0.984
3:39188633:C:G	W271C	0.984
3:39184806:A:G	L1547P	0.983
3:39188514:A:G	F311S	0.983
3:39188688:A:T	V253D	0.983
3:39188521:A:G	W309R	0.982
3:39188521:A:T	W309R	0.982
3:39188718:A:T	I243N	0.982

dbSNP variants (sampled 300 via entrez): RS1000020554 (3:39188141 C>A,G), RS1000159846 (3:39193227 C>T), RS1000720706 (3:39193447 G>A), RS1000878264 (3:39186130 C>G,T), RS1001089695 (3:39191133 T>C,G), RS1001992425 (3:39192225 C>A,G,T), RS1002409147 (3:39192277 T>C), RS1002663223 (3:39189574 T>A,G), RS1002732915 (3:39193853 G>A), RS1002947187 (3:39189381 A>C,G), RS1003012107 (3:39183245 G>A), RS1003106819 (3:39182880 A>G), RS1003281921 (3:39188499 A>G), RS1003445953 (3:39184354 T>C), RS1003508649 (3:39190608 C>A)

Disease associations

OMIM: gene MIM:609777 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002367_11	Social communication problems	9.000000e-09
GCST003075_110	Cognitive decline rate in late mild cognitive impairment	3.000000e-07
GCST003075_6	Cognitive decline rate in late mild cognitive impairment	5.000000e-08
GCST003518_42	Daytime sleep phenotypes	8.000000e-06
GCST010241_214	Apolipoprotein A1 levels	1.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005427	social communication impairment
EFO:0007710	cognitive decline measurement
EFO:0007828	daytime rest measurement
EFO:0004614	apolipoprotein A 1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
TL8-506	increases expression, affects cotreatment	1
bisphenol A	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, affects response to substance	1
abrine	increases expression	1
incobotulinumtoxinA	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	affects response to substance, affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Thiram	increases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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