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Authordc.contributor.authorGallego, Diana 
Authordc.contributor.authorLeal, Fatima 
Authordc.contributor.authorGámez, Alejandra 
Authordc.contributor.authorCastro, Margarita 
Authordc.contributor.authorNavarrete, Rosa 
Authordc.contributor.authorSánchez Lijarcio, Obdulia 
Authordc.contributor.authorVitoria, Isidro 
Authordc.contributor.authorBueno Delgado, María 
Authordc.contributor.authorBelanger Quintana, Amaya 
Authordc.contributor.authorMorais, Ana 
Authordc.contributor.authorPedrón Giner, Consuelo 
Authordc.contributor.authorGarcía, Inmaculada 
Authordc.contributor.authorCampistol, Jaume 
Authordc.contributor.authorArtuch, Rafael 
Authordc.contributor.authorAlcaide, Carlos 
Authordc.contributor.authorCornejo Espinoza, Verónica 
Authordc.contributor.authorGil, David 
Authordc.contributor.authorYahyaoui, Raquel 
Authordc.contributor.authorDesviat, Lourdes R. 
Authordc.contributor.authorUgarte, Magdalena 
Authordc.contributor.authorMartínez, Aurora 
Authordc.contributor.authorPérez, Belén 
Admission datedc.date.accessioned2020-06-09T21:57:47Z
Available datedc.date.available2020-06-09T21:57:47Z
Publication datedc.date.issued2020
Cita de ítemdc.identifier.citationHuman Mutation (Apr 2020)es_ES
Identifierdc.identifier.other10.1002/humu.24026
Identifierdc.identifier.urihttp://repositorio.uchile.cl/handle/2250/175368
Abstractdc.description.abstractBiallelic variants of the gene DNAJC12, which encodes a cochaperone, were recently described in patients with hyperphenylalaninemia (HPA). This paper reports the retrospective genetic analysis of a cohort of unsolved cases of HPA. Biallelic variants of DNAJC12 were identified in 20 patients (generally neurologically asymptomatic) previously diagnosed with phenylalanine hydroxylase (PAH) deficiency (phenylketonuria [PKU]). Further, mutations of DNAJC12 were identified in four carriers of a pathogenic variant of PAH. The genetic spectrum of DNAJC12 in the present patients included four new variants, two intronic changes c.298-2A>C and c.502+1G>C, presumably affecting the splicing process, and two exonic changes c.309G>T (p.Trp103Cys) and c.524G>A (p.Trp175Ter), classified as variants of unknown clinical significance (VUS). The variant p.Trp175Ter was detected in 83% of the mutant alleles, with 14 cases homozygous, and was present in 0.3% of a Spanish control population. Functional analysis indicated a significant reduction in PAH and its activity, reduced tyrosine hydroxylase stability, but no effect on tryptophan hydroxylase 2 stability, classifying the two VUS as pathogenic variants. Additionally, the effect of the overexpression of DNAJC12 on some destabilizing PAH mutations was examined and a mutation-specific effect on stabilization was detected suggesting that the proteostasis network could be a genetic modifier of PAH deficiency and a potential target for developing mutation-specific treatments for PKU.es_ES
Patrocinadordc.description.sponsorshipConsejería de Educación e Investigación: B2017/BMD-3721. Fundación Isabel Gemio-La Caixa: LCF/PR/PR16/11110018. Ministerio de Ciencia Tecnología y Telecomunicaciones PI16/00573.
Lenguagedc.language.isoenes_ES
Publisherdc.publisherWileyes_ES
Sourcedc.sourceHuman Mutationes_ES
Keywordsdc.subjectDNAJC12es_ES
Keywordsdc.subjectHyperphenylalaninemiaes_ES
Keywordsdc.subjectMolecular chaperoneses_ES
Keywordsdc.subjectPhenylketonuriaes_ES
Keywordsdc.subjectProteostasis networkes_ES
Keywordsdc.subjectPhenylketonuriaes_ES
Keywordsdc.subjectTetrahydrobiopterines_ES
Keywordsdc.subjectDeficiencyes_ES
Keywordsdc.subjectMutationses_ES
Keywordsdc.subjectDiagnosises_ES
Keywordsdc.subjectStabilityes_ES
Keywordsdc.subjectFamilyes_ES
Títulodc.titlePathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemiaes_ES
Document typedc.typeArtículo de revistaes_ES
Catalogueruchile.catalogadorrvhes_ES
Indexationuchile.indexArtículo de publicación ISIes_ES
Access notedct.AccessRightsSin acceso a texto completoes_ES


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