000048437 001__ 48437 000048437 005__ 20200221144246.0 000048437 0247_ $$2doi$$a10.1093/hmg/ddw004 000048437 0248_ $$2sideral$$a93812 000048437 037__ $$aART-2016-93812 000048437 041__ $$aeng 000048437 100__ $$0(orcid)0000-0002-3268-8730$$aEspinosa Angarica, Vladimir 000048437 245__ $$aExploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: Linking snps with disease phenotypes in familial hypercholesterolemia 000048437 260__ $$c2016 000048437 5060_ $$aAccess copy available to the general public$$fUnrestricted 000048437 5203_ $$aFamilial hypercholesterolemia (FH), a genetic disorder with a prevalence of 0.2%, represents a high-risk factor to develop cardiovascular and cerebrovascular diseases. The majority and most severe FH cases are associated to mutations in the receptor for low-density lipoproteins receptor (LDL-r), but the molecular basis explaining the connection between mutation and phenotype is often unknown, which hinders early diagnosis and treatment of the disease. We have used atomistic simulations to explore the complete SNP mutational space (227 mutants) of the LA5 repeat, the key domain for interacting with LDL that is coded in the exon concentrating the highest number of mutations. Four clusters of mutants of different stability have been identified. The majority of the 50 FH known mutations (33) appear distributed in the unstable clusters, i.e. loss of conformational stability explains two-third of FH phenotypes. However, one-third of FH phenotypes (17 mutations) do not destabilize the LR5 repeat. Combining our simulations with available structural data from different laboratories, we have defined a consensus-binding site for the interaction of the LA5 repeat with LDL-r partner proteins and have found that most (16) of the 17 stable FH mutations occur at binding site residues. Thus, LA5-associated FH arises from mutations that cause either the loss of stability or a decrease in domain's-binding affinity. Based on this finding, we propose the likely phenotype of each possible SNP in the LA5 repeat and outline a procedure to make a full computational diagnosis for FH. 000048437 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/BIO2012–32868$$9info:eu-repo/grantAgreement/ES/MINECO/BFU2013-47064-P$$9info:eu-repo/grantAgreement/ES/MICINN/BFU2010-16297 000048437 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttp://creativecommons.org/licenses/by-nc/3.0/es/ 000048437 590__ $$a5.34$$b2016 000048437 591__ $$aGENETICS & HEREDITY$$b23 / 166 = 0.139$$c2016$$dQ1$$eT1 000048437 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b46 / 287 = 0.16$$c2016$$dQ1$$eT1 000048437 592__ $$a3.698$$b2016 000048437 593__ $$aGenetics$$c2016$$dQ1 000048437 593__ $$aMolecular Biology$$c2016$$dQ1 000048437 593__ $$aMedicine (miscellaneous)$$c2016$$dQ1 000048437 593__ $$aGenetics (clinical)$$c2016$$dQ1 000048437 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000048437 700__ $$aOrozco, Modesto 000048437 700__ $$0(orcid)0000-0002-2879-9200$$aSancho Sanz, Javier$$uUniversidad de Zaragoza 000048437 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000048437 773__ $$g25, 6 (2016), 1233-1246$$pHum. mol. genet.$$tHUMAN MOLECULAR GENETICS$$x0964-6906 000048437 8564_ $$s1954412$$uhttps://zaguan.unizar.es/record/48437/files/texto_completo.pdf$$yVersión publicada 000048437 8564_ $$s100853$$uhttps://zaguan.unizar.es/record/48437/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000048437 909CO $$ooai:zaguan.unizar.es:48437$$particulos$$pdriver 000048437 951__ $$a2020-02-21-13:24:50 000048437 980__ $$aARTICLE