Author | dc.contributor.author | Gallego, Diana | |
Author | dc.contributor.author | Leal, Fatima | |
Author | dc.contributor.author | Gámez, Alejandra | |
Author | dc.contributor.author | Castro, Margarita | |
Author | dc.contributor.author | Navarrete, Rosa | |
Author | dc.contributor.author | Sánchez Lijarcio, Obdulia | |
Author | dc.contributor.author | Vitoria, Isidro | |
Author | dc.contributor.author | Bueno Delgado, María | |
Author | dc.contributor.author | Belanger Quintana, Amaya | |
Author | dc.contributor.author | Morais, Ana | |
Author | dc.contributor.author | Pedrón Giner, Consuelo | |
Author | dc.contributor.author | García, Inmaculada | |
Author | dc.contributor.author | Campistol, Jaume | |
Author | dc.contributor.author | Artuch, Rafael | |
Author | dc.contributor.author | Alcaide, Carlos | |
Author | dc.contributor.author | Cornejo Espinoza, Verónica | |
Author | dc.contributor.author | Gil, David | |
Author | dc.contributor.author | Yahyaoui, Raquel | |
Author | dc.contributor.author | Desviat, Lourdes R. | |
Author | dc.contributor.author | Ugarte, Magdalena | |
Author | dc.contributor.author | Martínez, Aurora | |
Author | dc.contributor.author | Pérez, Belén | |
Admission date | dc.date.accessioned | 2020-06-09T21:57:47Z | |
Available date | dc.date.available | 2020-06-09T21:57:47Z | |
Publication date | dc.date.issued | 2020 | |
Cita de ítem | dc.identifier.citation | Human Mutation (Apr 2020) | es_ES |
Identifier | dc.identifier.other | 10.1002/humu.24026 | |
Identifier | dc.identifier.uri | https://repositorio.uchile.cl/handle/2250/175368 | |
Abstract | dc.description.abstract | Biallelic 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 |
Patrocinador | dc.description.sponsorship | Consejería de Educación e Investigación: B2017/BMD-3721. Fundación Isabel Gemio-La Caixa: LCF/PR/PR16/11110018. Ministerio de Ciencia Tecnología y Telecomunicaciones PI16/00573. | |
Lenguage | dc.language.iso | en | es_ES |
Publisher | dc.publisher | Wiley | es_ES |
Source | dc.source | Human Mutation | es_ES |
Keywords | dc.subject | DNAJC12 | es_ES |
Keywords | dc.subject | Hyperphenylalaninemia | es_ES |
Keywords | dc.subject | Molecular chaperones | es_ES |
Keywords | dc.subject | Phenylketonuria | es_ES |
Keywords | dc.subject | Proteostasis network | es_ES |
Keywords | dc.subject | Phenylketonuria | es_ES |
Keywords | dc.subject | Tetrahydrobiopterin | es_ES |
Keywords | dc.subject | Deficiency | es_ES |
Keywords | dc.subject | Mutations | es_ES |
Keywords | dc.subject | Diagnosis | es_ES |
Keywords | dc.subject | Stability | es_ES |
Keywords | dc.subject | Family | es_ES |
Título | dc.title | Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia | es_ES |
Document type | dc.type | Artículo de revista | es_ES |
dcterms.accessRights | dcterms.accessRights | Acceso a solo metadatos | es_ES |
Cataloguer | uchile.catalogador | rvh | es_ES |
Indexation | uchile.index | Artículo de publicación ISI | |
Indexation | uchile.index | Artículo de publicación SCOPUS | |