ITGB1BP2

Summary

ITGB1BP2 (integrin subunit beta 1 binding protein 2, HGNC:6154) is a protein-coding gene on chromosome Xq13.1, encoding Integrin beta-1-binding protein 2 (Q9UKP3). May play a role during maturation and/or organization of muscles cells.

This gene encodes a protein with two cysteine and histidine-rich (CHORD) domains, PXXP motifs, YXXI/P motifs, putative SH2 and SH3 domain binding motifs, and an acidic region at the C-terminus that can bind calcium. Two hybrid analysis showed that this protein interacts with the cytoplasmic domain of the beta 1 integrin subunit and is thought to act as a chaperone protein. Studies in the mouse ortholog of this gene indicate that absence of this gene in mouse results in failed cardiac hypertrophy in response to mechanical stress. Alternative splicing results in multiple transcript variants encoding different isoforms, including an isoform that lacks several domains, including one of the CHORD domains.

Source: NCBI Gene 26548 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 72 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_012278

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6154
Approved symbol	ITGB1BP2
Name	integrin subunit beta 1 binding protein 2
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	CHORDC3
Ensembl gene	ENSG00000147166
Ensembl biotype	protein_coding
OMIM	300332
Entrez	26548

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000373829, ENST00000465388, ENST00000475413, ENST00000483897, ENST00000538820, ENST00000970298, ENST00000970299, ENST00000970300

RefSeq mRNA: 2 — MANE Select: NM_012278 NM_001303277, NM_012278

CCDS: CCDS14411

Canonical transcript exons

ENST00000373829 — 11 exons

Exon	Start	End
ENSE00000979086	71302137	71302186
ENSE00000979087	71302277	71302333
ENSE00000979088	71302411	71302556
ENSE00000979094	71304542	71304604
ENSE00001461681	71304965	71305371
ENSE00001854324	71301750	71301870
ENSE00003474750	71303461	71303516
ENSE00003500159	71304187	71304300
ENSE00003632902	71303262	71303356
ENSE00003679270	71303812	71303911
ENSE00003688564	71303627	71303697

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 97.22.

FANTOM5 (CAGE): breadth broad, TPM avg 1.1172 / max 113.5445, expressed in 235 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196681	1.0477	215
196680	0.0695	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right atrium auricular region	UBERON:0006631	97.22	gold quality
cardiac atrium	UBERON:0002081	96.85	gold quality
heart right ventricle	UBERON:0002080	95.91	gold quality
apex of heart	UBERON:0002098	95.90	gold quality
heart left ventricle	UBERON:0002084	95.79	gold quality
cardiac ventricle	UBERON:0002082	95.66	gold quality
left ventricle myocardium	UBERON:0006566	94.54	gold quality
heart	UBERON:0000948	94.43	gold quality
myocardium	UBERON:0002349	94.07	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.60	gold quality
triceps brachii	UBERON:0001509	92.29	gold quality
biceps brachii	UBERON:0001507	92.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.31	gold quality
vastus lateralis	UBERON:0001379	90.75	gold quality
vena cava	UBERON:0004087	90.73	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.40	gold quality
quadriceps femoris	UBERON:0001377	90.26	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.38	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.49	gold quality
skeletal muscle tissue	UBERON:0001134	88.07	gold quality
muscle tissue	UBERON:0002385	88.04	gold quality
diaphragm	UBERON:0001103	87.63	silver quality
muscle organ	UBERON:0001630	87.21	gold quality
body of tongue	UBERON:0011876	86.47	gold quality
muscle of leg	UBERON:0001383	86.29	gold quality
gastrocnemius	UBERON:0001388	86.24	gold quality
deltoid	UBERON:0001476	85.03	gold quality
ascending aorta	UBERON:0001496	84.06	gold quality
thoracic aorta	UBERON:0001515	84.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	83.51	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-100618	no	97.75
E-ANND-3	no	2.30

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting ITGB1BP2, 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-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4273	99.45	67.93	1206
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-7158-5P	99.25	67.95	796
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-4520-2-3P	99.14	69.28	1009
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-4521	97.73	67.64	684
HSA-MIR-4475	97.36	66.95	761
HSA-MIR-6892-5P	97.27	68.60	847
HSA-MIR-370-3P	97.09	64.92	1221

Literature-anchored findings (GeneRIF, showing 5)

• Studies in mouse show that melusin prevents cardiac dilation during chronic pressure overload by specifically sensing mechanical stress. (PMID:12496958)
• Our analysis revealed an extremely low number of variations in the ITGB1BP2 gene in nearly 1000 hypertensive/cardiopathic and healthy individuals, thus suggesting a high degree of conservation of the melusin gene within the populations analyzed (PMID:20017903)
• The altered melusin pathways and CDC42 parallel the cardiac function progression during cardiac remodeling post-MI. (PMID:21546274)
• Identification of a missense mutation in the melusin-encoding ITGB1BP2 gene in a patient with dilated cardiomyopathy (PMID:23124043)
• Chp-1 and melusin can interact with cochaperones PP5 and Sgt1 and with each other in an ATP-dependent manner (PMID:23184943)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:92429	ENSDARG00000030176
mus_musculus	Itgb1bp2	ENSMUSG00000031312
rattus_norvegicus	Itgb1bp2	ENSRNOG00000003596
drosophila_melanogaster	mora	FBGN0029503
caenorhabditis_elegans	chp-1	WBGENE00000502

Paralogs (1): CHORDC1 (ENSG00000110172)

Protein

Protein identifiers

Integrin beta-1-binding protein 2 — Q9UKP3 (reviewed: Q9UKP3)

Alternative names: Melusin

All UniProt accessions (1): Q9UKP3

UniProt curated annotations — full annotation on UniProt →

Function. May play a role during maturation and/or organization of muscles cells.

Subunit / interactions. Interacts with beta-1 integrin subunit. This interaction is regulated by divalent cations, and it occurs only in absence of calcium.

Tissue specificity. Expressed in skeletal and cardiac muscles but not in other tissues.

Domain organisation. The tail domain binds to the cytoplasmic domain of both integrin beta-1a and beta-1d isoforms. The presence of Ca(2+) ions does not prevent binding of a fragment consisting of the second cysteine rich repeat and the tail domain but prevents the binding of the full-length protein.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UKP3-1	1	yes
Q9UKP3-2	2

RefSeq proteins (2): NP_001290206, NP_036410* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007051	CHORD_dom	Domain
IPR007052	CS_dom	Domain
IPR008978	HSP20-like_chaperone	Homologous_superfamily
IPR039790	CHRD1	Family

Pfam: PF04968, PF04969

UniProt features (28 total): binding site 16, short sequence motif 5, domain 3, chain 1, compositionally biased region 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKP3-F1	79.26	0.44

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 (16): 5; 10; 24; 27; 42; 43; 59; 64; 149; 154; 168; 171 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 101 (showing top): GCANCTGNY_MYOD_Q6, TGACCTY_ERR1_Q2, CAGCTG_AP4_Q5, SRF_Q5_01, SRF_01, SRF_C, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, WTGAAAT_UNKNOWN, CCCNNNNNNAAGWT_UNKNOWN, TATA_C, KIM_GASTRIC_CANCER_CHEMOSENSITIVITY, HAND1E47_01, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_CENTROSOME_DUPLICATION, EBAUER_MYOGENIC_TARGETS_OF_PAX3_FOXO1_FUSION

GO Biological Process (3): signal transduction (GO:0007165), muscle organ development (GO:0007517), centrosome duplication (GO:0051298)

GO Molecular Function (6): integrin binding (GO:0005178), calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), SH3 domain binding (GO:0017124), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (1): Z disc (GO:0030018)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
animal organ development	1
muscle structure development	1
centrosome cycle	1
cell cycle process	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
metal ion binding	1
transition metal ion binding	1
protein domain specific binding	1
binding	1
cation binding	1
I band	1
cellular anatomical structure	1

Protein interactions and networks

STRING

832 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITGB1BP2	ITGB1	P05556	867
ITGB1BP2	SMPX	Q9UHP9	858
ITGB1BP2	PDK3	Q15120	829
ITGB1BP2	IQGAP1	P46940	723
ITGB1BP2	PDHA1	P08559	683
ITGB1BP2	MAP2K1	Q02750	653
ITGB1BP2	HSP90AA1	P07900	648
ITGB1BP2	HSP90AB1	P08238	636
ITGB1BP2	FOXO4	P98177	587
ITGB1BP2	CALR	P27797	536
ITGB1BP2	RAF1	P04049	529
ITGB1BP2	GSK3B	P49841	512
ITGB1BP2	MAPK3	P27361	510
ITGB1BP2	AGT	P01019	508
ITGB1BP2	PXN	P49023	494

IntAct

23 interactions, top by confidence:

A	B	Type	Score
ITGB1BP2	PDCD2L	psi-mi:“MI:0915”(physical association)	0.690
ITGB1BP2	RARA	psi-mi:“MI:0915”(physical association)	0.500
ITGB1BP2	RARG	psi-mi:“MI:0915”(physical association)	0.400
ITGB1BP2	N	psi-mi:“MI:0915”(physical association)	0.370
ITGB1BP2	rep	psi-mi:“MI:0915”(physical association)	0.370
ITGB1BP2		psi-mi:“MI:0915”(physical association)	0.370
ITGB1BP2	S	psi-mi:“MI:0915”(physical association)	0.370
ITGB1BP2	PLOD2	psi-mi:“MI:0914”(association)	0.350
HSP90AA1	ITGB1BP2	psi-mi:“MI:0915”(physical association)	0.000
ITGB1BP2	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.000
ITGB1BP2	PUM3	psi-mi:“MI:0915”(physical association)	0.000
ITGB1BP2	PPHLN1	psi-mi:“MI:0915”(physical association)	0.000
SH3GLB1	ITGB1BP2	psi-mi:“MI:0915”(physical association)	0.000
STAG2	ITGB1BP2	psi-mi:“MI:0915”(physical association)	0.000
TKT	ITGB1BP2	psi-mi:“MI:0915”(physical association)	0.000
TTN	ITGB1BP2	psi-mi:“MI:0915”(physical association)	0.000
UGDH	ITGB1BP2	psi-mi:“MI:0915”(physical association)	0.000
ITGB1BP2	WASL	psi-mi:“MI:0915”(physical association)	0.000
SGCA	ITGB1BP2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (42): PDCD2L (Affinity Capture-MS), PDCD2L (Affinity Capture-MS), HSP90AA1 (Two-hybrid), HSP90AB1 (Two-hybrid), KIAA0020 (Two-hybrid), SH3GLB1 (Two-hybrid), PPHLN1 (Two-hybrid), STAG2 (Two-hybrid), UGDH (Two-hybrid), WASL (Two-hybrid), TKT (Two-hybrid), TTN (Two-hybrid), ITGB1BP2 (Two-hybrid), PDCD2L (Affinity Capture-MS), ITGB1BP2 (Two-hybrid)

ESM2 similar proteins: A2YEZ6, A3BDI8, A9YUB1, D4A4T9, E7EZF3, G5EEI8, O89042, P09874, P11103, P18493, P23881, P26446, P27008, P31669, P40818, P48724, P55010, P59325, Q07205, Q08446, Q17QE2, Q29RL2, Q2KI09, Q462R2, Q4R7U2, Q5PXT2, Q5R4L0, Q5RD91, Q5ZML4, Q6DFN7, Q6GLZ1, Q6NUA0, Q7T3F7, Q7Y1W9, Q852K5, Q8H0X0, Q8VDF2, Q8VEE1, Q9C8F1, Q9CQJ6

Diamond homologs: A9YUB1, D4A4T9, G5EEI8, Q0JL44, Q29RL2, Q462R2, Q4R7U2, Q55ED0, Q5RD91, Q5ZML4, Q6EPW7, Q6NUA0, Q7T3F7, Q9D1P4, Q9R000, Q9SE33, Q9SUR9, Q9SUT5, Q9UHD1, Q9UKP3, Q9VCC0, A0A3L6DPG1, B0BN85, Q28CZ9, Q9Y2Z0, O59709, Q08446, Q2KIK0, Q9CX34

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	38
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
4072240	GRCh37/hg19 Xq13.1(chrX:70479500-70541202)x0	Pathogenic
4086088	Single allele	Likely pathogenic

SpliceAI

909 predictions. Top by Δscore:

Variant	Effect	Δscore
X:71301869:TG:T	donor_gain	1.0000
X:71301869:TGG:T	donor_loss	1.0000
X:71301870:GG:G	donor_gain	1.0000
X:71301871:G:GG	donor_gain	1.0000
X:71301872:T:A	donor_loss	1.0000
X:71302557:G:GG	donor_gain	1.0000
X:71302565:G:GT	donor_gain	1.0000
X:71302568:G:GT	donor_gain	1.0000
X:71303256:CCCTA:C	acceptor_loss	1.0000
X:71303257:CCTA:C	acceptor_loss	1.0000
X:71303258:CTA:C	acceptor_loss	1.0000
X:71303259:TAG:T	acceptor_loss	1.0000
X:71303261:G:A	acceptor_loss	1.0000
X:71303261:GGTCA:G	acceptor_gain	1.0000
X:71303354:CAGG:C	donor_loss	1.0000
X:71303355:AGG:A	donor_loss	1.0000
X:71303356:GG:G	donor_loss	1.0000
X:71303357:G:GA	donor_loss	1.0000
X:71303358:T:G	donor_loss	1.0000
X:71303456:CCCA:C	acceptor_loss	1.0000
X:71303457:CCAG:C	acceptor_loss	1.0000
X:71303459:A:AG	acceptor_gain	1.0000
X:71303460:G:GG	acceptor_gain	1.0000
X:71303460:G:GT	acceptor_loss	1.0000
X:71303514:GCT:G	donor_gain	1.0000
X:71303517:G:GG	donor_gain	1.0000
X:71303695:GGG:G	donor_gain	1.0000
X:71303696:GGG:G	donor_gain	1.0000
X:71304541:GCTTC:G	acceptor_gain	1.0000
X:71301866:TCCTG:T	donor_gain	0.9900

AlphaMissense

2287 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:71303687:T:C	F177L	0.998
X:71303689:C:A	F177L	0.998
X:71303689:C:G	F177L	0.998
X:71303669:C:G	H171D	0.996
X:71302169:T:C	F33L	0.995
X:71302171:C:A	F33L	0.995
X:71302171:C:G	F33L	0.995
X:71302319:T:C	F53L	0.995
X:71302321:C:A	F53L	0.995
X:71302321:C:G	F53L	0.995
X:71303861:T:C	F197L	0.994
X:71303863:C:A	F197L	0.994
X:71303863:C:G	F197L	0.994
X:71304983:A:C	S279R	0.994
X:71304985:C:A	S279R	0.994
X:71304985:C:G	S279R	0.994
X:71302186:G:C	K38N	0.993
X:71302186:G:T	K38N	0.993
X:71303671:C:A	H171Q	0.993
X:71303671:C:G	H171Q	0.993
X:71303818:G:C	K182N	0.993
X:71303818:G:T	K182N	0.993
X:71302310:T:C	F50L	0.992
X:71302312:C:A	F50L	0.992
X:71302312:C:G	F50L	0.992
X:71303688:T:C	F177S	0.991
X:71303688:T:G	F177C	0.991
X:71303852:T:C	F194L	0.991
X:71303854:T:A	F194L	0.991
X:71303854:T:G	F194L	0.991

dbSNP variants (sampled 300 via entrez): RS1000131078 (X:71300228 G>A,T), RS1000182270 (X:71300659 G>A), RS1001609325 (X:71301609 C>A,G), RS1004411687 (X:71300027 G>A), RS1005112783 (X:71300157 G>A), RS1006534820 (X:71302839 A>T), RS1007485447 (X:71304902 T>A), RS1008229260 (X:71303659 A>C,G), RS1008855219 (X:71301208 G>C), RS1009993759 (X:71302935 G>A), RS1010291966 (X:71303296 A>C), RS1011332946 (X:71304398 A>G), RS1011408586 (X:71303881 C>T), RS1012415958 (X:71300242 G>A), RS1015474111 (X:71301359 A>G)

Disease associations

OMIM: gene MIM:300332 | disease phenotypes: MIM:300967

GenCC curated gene-disease

Mondo (1): syndromic X-linked intellectual disability 34 (MONDO:0010501)

Orphanet (1): Macrocephaly-intellectual disability-left ventricular non compaction syndrome (Orphanet:466791)

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
bisphenol A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
incobotulinumtoxinA	decreases expression	1
Sunitinib	decreases expression	1
Adenosine Triphosphate	increases reaction, affects binding	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcium	affects binding, increases reaction	1
Doxorubicin	affects expression	1
Methyl Methanesulfonate	decreases expression	1
Silicon Dioxide	increases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Vincristine	decreases expression	1

Clinical trials (associated diseases)

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