Alternative titles; symbols
HGNC Approved Gene Symbol: ITGB1BP2
Cytogenetic location: Xq13.1 Genomic coordinates (GRCh38): X:71,301,750-71,305,371 (from NCBI)
To identify muscle proteins capable of interacting with the beta-1 integrin (135630) cytoplasmic domain, Brancaccio et al. (1999) isolated cDNAs from a rat neonatal heart cDNA library using the cytoplasmic region of beta-1 integrin isoforms as bait. Using a fragment of a rat cDNA as probe, they isolated human and mouse full-length melusin, or beta-1 integrin-binding protein-2, cDNAs from human and mouse skeletal muscle libraries. The human ITGB1BP2 cDNA encodes a deduced 347-amino acid protein that shares 92% sequence identity with the mouse homolog. Its C terminus contains an acidic region resembling the calreticulin and calsequestrin C-domain, which is known to bind calcium, and the N terminus contains 2 cysteine-rich repeats. The predicted protein also has putative binding sites for SH3 and SH2 domains. Northern blot analysis of human tissues detected restricted expression of a 1.4-kb ITGB1BP2 transcript in skeletal and cardiac muscles. An identical expression pattern was found in mouse tissues. Northern and Western blot analysis of a murine myogenic cell line showed that expression is absent in undifferentiated myoblasts but is turned on in differentiating myotubes and during muscle regeneration. Studies in mouse showed that ITGB1BP2 expression is detectable in embryo limbs at day 15, reaches maximum level in newborn mice, and declines in adult limb muscle, whereas its level remains unchanged during heart development from embryonic to adult stage. Interaction of ITGB1BP2 with integrin is specific for the beta-1 subunits and involves the tail region of ITGB1BP2 and a 26-amino acid cytoplasmic subdomain common to all beta-1 isoforms. In vitro binding assays showed that the interaction of ITGB1BP2 and integrin heterodimers occurs only in the absence of Ca(2+), suggesting that such interaction is regulated by intracellular signals affecting Ca(2+) concentration.
By FISH, Brancaccio et al. (1999) mapped the human ITGB1BP2 gene to Xq12.1-q13 and the corresponding mouse gene to the X chromosome at band D.
See 300332.0001 for discussion of a possible association between dilated cardiomyopathy (CMD; see 115200) and mutation in the ITGB1BP2 gene.
Cardiac hypertrophy is an adaptive response to a variety of mechanical and hormonal stimuli, and represents an early event in the clinical course leading to heart failure. By gene inactivation, Brancaccio et al. (2003) demonstrated a crucial role of melusin in the hypertrophic response to mechanical overload. Melusin-null mice showed normal cardiac structure and function under physiologic conditions, but when subjected to pressure overload--a condition that induces a hypertrophic response in wildtype controls--they developed an abnormal cardiac remodeling that evolved into dilated cardiomyopathy and contractile dysfunction. In contrast, the hypertrophic response was identical in wildtype and melusin-null mice after chronic administration of angiotensin II or phenylephrine at doses that do not increase blood pressure--i.e., in the absence of cardiac biomechanical stress. Analysis of intracellular signaling events induced by pressure overload indicated that phosphorylation of glycogen synthase kinase-3-beta (GSK3B; 605004) was specifically blunted in melusin-null hearts. Thus, melusin prevents cardiac dilation during chronic pressure overload by specifically sensing mechanical stress.
This variant is classified as a variant of unknown significance because its contribution to dilated cardiomyopathy (CMD; see 115200) has not been confirmed.
In a 45-year-old man with severe dilated cardiomyopathy, Ruppert et al. (2013) identified a c.938C-G transversion in exon 11 of the ITGB1BP2 gene, resulting in an ala313-to-gly (A313G) substitution at a residue located within a spacer region between the CS domain and the Ca(2+)-binding C-terminal acidic domain. The mutation was also detected in his affected 46-year-old sister, but not in 2 unaffected sibs or in 300 controls. The proband had a severely reduced left ventricular ejection fraction (LVEF) of 20% and increased end-diastolic left ventricular diameter (LVEDD) of 74 mm. Histologic analysis of endomyocardial biopsies showed hypertrophic cardiomyocytes with size variability and significant deposition of fibrotic tissue in the interstitium. His sister was diagnosed as having borderline CMD, with a slightly reduced ejection fraction of 50% and slightly increased LVEDD of 58 mm on echocardiography. Both sibs as well as 6 additional family members had sensorineural hearing loss; there was no association between diagnosis of CMD and hearing loss. Screening of DNA from the proband for variation in 21 other genes known or suspected to be associated with CMD also revealed SNPs or mutations in 4 of them.
Brancaccio, M., Fratta, L., Notte, A., Hirsch, E., Poulet, R., Guazzone, S., De Acetis, M., Vecchione, C., Marino, G., Altruda, F., Silengo, L., Tarone, G., Lembo, G. Melusin, a muscle-specific integrin beta-1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload. Nature Med. 9: 68-75, 2003. [PubMed: 12496958] [Full Text: https://doi.org/10.1038/nm805]
Brancaccio, M., Guazzone, S., Menini, N., Sibona, E., Hirsch, E., De Andrea, M., Rocchi, M., Altruda, F., Tarone, G., Silengo, L. Melusin is a new muscle-specific interactor for beta 1 integrin cytoplasmic domain. J. Biol. Chem. 274: 29282-29288, 1999. [PubMed: 10506186] [Full Text: https://doi.org/10.1074/jbc.274.41.29282]
Ruppert, V., Meyer, T., Richter, A., Maisch, B., Pankuweit, S. Identification of a missense mutation in the melusin-encoding ITGB1BP2 gene in a patient with dilated cardiomyopathy. Gene 512: 206-210, 2013. [PubMed: 23124043] [Full Text: https://doi.org/10.1016/j.gene.2012.10.055]