000130806 001__ 130806
000130806 005__ 20240131210811.0
000130806 0247_ $$2doi$$a10.1016/j.jbc.2021.100854
000130806 0248_ $$2sideral$$a126576
000130806 037__ $$aART-2021-126576
000130806 041__ $$aeng
000130806 100__ $$aSuay-Corredera C.
000130806 245__ $$aProtein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy
000130806 260__ $$c2021
000130806 5060_ $$aAccess copy available to the general public$$fUnrestricted
000130806 5203_ $$aHypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM. © 2021 THE AUTHORS.
000130806 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000130806 590__ $$a5.485$$b2021
000130806 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b94 / 297 = 0.316$$c2021$$dQ2$$eT1
000130806 592__ $$a1.871$$b2021
000130806 593__ $$aCell Biology$$c2021$$dQ1
000130806 593__ $$aBiochemistry$$c2021$$dQ1
000130806 594__ $$a8.8$$b2021
000130806 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000130806 700__ $$aPricolo M.R.
000130806 700__ $$aHerrero-Galán E.
000130806 700__ $$aVelázquez-Carreras D.
000130806 700__ $$aSánchez-Ortiz D.
000130806 700__ $$aGarcía-Giustiniani D.
000130806 700__ $$aDelgado J.
000130806 700__ $$0(orcid)0000-0002-1896-7805$$aGalano-Frutos J.J.
000130806 700__ $$0(orcid)0000-0002-9590-7371$$aGarcía Cebollada H.$$uUniversidad de Zaragoza
000130806 700__ $$aVilches S.
000130806 700__ $$aDomínguez F.
000130806 700__ $$aMolina M.S.
000130806 700__ $$aBarriales-Villa R.
000130806 700__ $$aFrisso G.
000130806 700__ $$0(orcid)0000-0002-2879-9200$$aSancho Sanz J.$$uUniversidad de Zaragoza
000130806 700__ $$aSerrano L.
000130806 700__ $$aGarcía-Pavía P.
000130806 700__ $$aMonserrat L.
000130806 700__ $$aAlegre-Cebollada J.
000130806 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000130806 773__ $$g297, 1 (2021), 100854 [14 pp]$$pJ. biol. chem.$$tJournal of Biological Chemistry$$x0021-9258
000130806 8564_ $$s1943293$$uhttps://zaguan.unizar.es/record/130806/files/texto_completo.pdf$$yVersión publicada
000130806 8564_ $$s3623000$$uhttps://zaguan.unizar.es/record/130806/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000130806 909CO $$ooai:zaguan.unizar.es:130806$$particulos$$pdriver
000130806 951__ $$a2024-01-31-19:22:55
000130806 980__ $$aARTICLE