Top

Published in:

Open Access 01-12-2009 | Research article

Melusin gene (ITGB1BP2) nucleotide variations study in hypertensive and cardiopathic patients

Authors: Valeria Palumbo, Ludovica Segat, Lara Padovan, Antonio Amoroso, Bruno Trimarco, Raffaele Izzo, Giuseppe Lembo, Vera Regitz–Zagrosek, Ralph Knoll, Mara Brancaccio, Guido Tarone, Sergio Crovella

Published in: BMC Medical Genetics | Issue 1/2009

Abstract

Background

Melusin is a muscle specific signaling protein, required for compensatory hypertrophy response in pressure-overloaded heart. The role of Melusin in heart function has been established both by loss and gain of function experiments in murine models. With the aim of verifying the hypothesis of a potential role of the Melusin encoding gene, ITGB1BP2, in the modification of the clinical phenotype of human cardiomyopathies, we screened the ITGB1BP2 gene looking for genetic variations possibly associated to the pathological phenotype in three selected groups of patients affected by hypertension and dilated or hypertrophic cardiomyopathy

Methods

We analyzed ITGB1BP2 by direct sequencing of the 11 coding exons and intron flanking sequences in 928 subjects, including 656 hypertensive or cardiopathic patients and 272 healthy individuals.

Results

Only three nucleotide variations were found in patients of three distinct families: a C>T missense substitution at position 37 of exon 1 causing an amino acid change from His-13 to Tyr in the protein primary sequence, a duplication (IVS6+12_18dupTTTTGAG) near the 5'donor splice site of intron 6, and a silent 843C>T substitution in exon 11.

Conclusions

The three variations of the ITGB1BP2 gene have been detected in families of patients affected either by hypertension or primary hypertrophic cardiomyopathy; however, a clear genotype/phenotype correlation was not evident. Preliminary functional results and bioinformatic analysis seem to exclude a role for IVS6+12_18dupTTTTGAG and 843C>T in affecting splicing mechanism.

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.

Available only for authorised users

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. 1999, 274: 29282-8. 10.1074/jbc.274.41.29282.CrossRefPubMed

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 beta1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload. Nat Med. 2003, 9: 68-75. 10.1038/nm805.CrossRefPubMed

De Acetis M, Notte A, Accornero F, Selvetella G, Brancaccio M, Vecchione C, Sbroggiò M, Collino F, Pacchioni B, Lanfranchi G, Aretini A, Ferretti R, Maffei A, Altruda F, Silengo L, Tarone G, Lembo G: Cardiac overexpression of melusin protects from dilated cardiomyopathy due to long-standing pressure overload. Circ Res. 2005, 96: 1087-94. 10.1161/01.RES.0000168028.36081.e0.CrossRefPubMed

Brokat S, Thomas J, Herda LR, Knosalla C, Pregla R, Brancaccio M, Accornero F, Tarone G, Hetzer R, Regitz-Zagrosek V: Altered melusin expression in the hearts of aortic stenosis patients. Eur J Heart Fail. 2007, 9 (6-7): 568-73. 10.1016/j.ejheart.2007.02.009.CrossRefPubMed

Dorn GW, Force T: Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest. 2005, 115: 527-37.CrossRefPubMedPubMedCentral

Brancaccio M, Hirsch E, Notte A, Selvetella G, Lembo G, Tarone G: Integrin signalling: the tug-of-war in heart hypertrophy. Cardiovasc Res. 2006, 70: 422-33. 10.1016/j.cardiores.2005.12.015.CrossRefPubMed

Heineke J, Molkentin JD: Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006, 7: 589-600. 10.1038/nrm1983.CrossRefPubMed

Daehmlow S, Erdmann J, Knueppel T, Gille C, Froemmel C, Hummel M, Hetzer R, Regitz-Zagrosek V: Novel mutations in sarcomeric protein genes in dilated cardiomyopathy. Biochem Biophys Res Commun. 2002, 298 (1): 116-20. 10.1016/S0006-291X(02)02374-4.CrossRefPubMed

Erdmann J, Raible J, Maki-Abadi J, Hummel M, Hammann J, Wollnik B, Frantz E, Fleck E, Hetzer R, Regitz-Zagrosek V: Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2001, 38 (2): 322-3. 10.1016/S0735-1097(01)01387-0.CrossRefPubMed

10.

Erdmann J, Daehmlow S, Wischke S, Senyuva M, Werner U, Raible J, Tanis N, Dyachenko S, Hummel M, Hetzer R, Regitz-Zagrosek V: Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet. 2003, 64 (4): 339-49. 10.1034/j.1399-0004.2003.00151.x.CrossRefPubMed

11.

Barki-Harrington L, Rockman HA: Sensing heart stress. Nat Med. 2003, 9 (1): 19-20. 10.1038/nm0103-19.CrossRefPubMed

12.

Cartegni L, Chew SL, Krainer AR: Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet. 2002, 3: 285-98. 10.1038/nrg775.CrossRefPubMed

13.

Fairbrother WG, Yeh RF, Sharp PA, Burge CB: Predictive identification of exonic splicing enhancers in human genes. Science. 2002, 297: 1007-13. 10.1126/science.1073774.CrossRefPubMed

14.

Riveira-Munoz E, Chang Q, Godefroid N, Hoenderop JG, Bindels RJ, Dahan K, Devuyst O: Belgian Network for Study of Gitelman Syndrome.:Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. J Am Soc Nephrol. 2007, 18: 1271-1283. 10.1681/ASN.2006101095.CrossRefPubMed

15.

Khajavi M, Inoue K, Lupski JR: Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur J Hum Genet. 2006, 14 (10): 1074-81. 10.1038/sj.ejhg.5201649.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/10/140/prepub

Title: Melusin gene (ITGB1BP2) nucleotide variations study in hypertensive and cardiopathic patients
Authors: Valeria Palumbo
Ludovica Segat
Lara Padovan
Antonio Amoroso
Bruno Trimarco
Raffaele Izzo
Giuseppe Lembo
Vera Regitz–Zagrosek
Ralph Knoll
Mara Brancaccio
Guido Tarone
Sergio Crovella
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2009
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/1471-2350-10-140

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Melusin gene (ITGB1BP2) nucleotide variations study in hypertensive and cardiopathic patients

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2009

Novel quantitative trait locus is mapped to chromosome 12p11 for left ventricular mass in Dominican families: the Family Study of Stroke Risk and Carotid Atherosclerosis

A mitotic recombination map proximal to the APC locus on chromosome 5q and assessment of influences on colorectal cancer risk

Association of APOEpolymorphism with chronic kidney disease in a nationally representative sample: a Third National Health and Nutrition Examination Survey (NHANES III) Genetic Study

The first Dutch SDHB founder deletion in paraganglioma – pheochromocytoma patients

A pooling-based genome-wide analysis identifies new potential candidate genes for atopy in the European Community Respiratory Health Survey (ECRHS)

ACE (I/D) polymorphism and response to treatment in coronary artery disease: a comprehensive database and meta-analysis involving study quality evaluation