Publication: Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia.
dc.contributor.author | Gallego, Diana | |
dc.contributor.author | Leal, Fátima | |
dc.contributor.author | Gámez, Alejandra | |
dc.contributor.author | Castro, Margarita | |
dc.contributor.author | Navarrete, Rosa | |
dc.contributor.author | Sanchez-Lijarcio, Obdulia | |
dc.contributor.author | Vitoria, Isidro | |
dc.contributor.author | Bueno-Delgado, María | |
dc.contributor.author | Belanger-Quintana, Amaya | |
dc.contributor.author | Morais, Ana | |
dc.contributor.author | Pedrón-Giner, Consuelo | |
dc.contributor.author | García, Inmaculada | |
dc.contributor.author | Campistol, Jaume | |
dc.contributor.author | Artuch, Rafael | |
dc.contributor.author | Alcaide, Carlos | |
dc.contributor.author | Cornejo, Veronica | |
dc.contributor.author | Gil, David | |
dc.contributor.author | Yahyaoui, Raquel | |
dc.contributor.author | Desviat, Lourdes R | |
dc.contributor.author | Ugarte, Magdalena | |
dc.contributor.author | Martínez, Aurora | |
dc.contributor.author | Pérez, Belén | |
dc.date.accessioned | 2023-02-08T14:47:12Z | |
dc.date.available | 2023-02-08T14:47:12Z | |
dc.date.issued | 2020-04-30 | |
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. | |
dc.identifier.doi | 10.1002/humu.24026 | |
dc.identifier.essn | 1098-1004 | |
dc.identifier.pmid | 32333439 | |
dc.identifier.unpaywallURL | https://repositorio.uam.es/bitstream/10486/690974/1/pathogenic_gallego_HM_2020ps.pdf | |
dc.identifier.uri | http://hdl.handle.net/10668/15431 | |
dc.issue.number | 7 | |
dc.journal.title | Human mutation | |
dc.journal.titleabbreviation | Hum Mutat | |
dc.language.iso | en | |
dc.organization | Hospital Universitario Regional de Málaga | |
dc.organization | Instituto de Investigación Biomédica de Málaga-IBIMA | |
dc.organization | Hospital Universitario Virgen del Rocío | |
dc.page.number | 1329-1338 | |
dc.pubmedtype | Journal Article | |
dc.pubmedtype | Research Support, Non-U.S. Gov't | |
dc.rights.accessRights | open access | |
dc.subject | DNAJC12 | |
dc.subject | hyperphenylalaninemia | |
dc.subject | molecular chaperones | |
dc.subject | phenylketonuria | |
dc.subject | proteostasis network | |
dc.subject.mesh | Adolescent | |
dc.subject.mesh | Adult | |
dc.subject.mesh | Alleles | |
dc.subject.mesh | Child | |
dc.subject.mesh | Child, Preschool | |
dc.subject.mesh | DNA Mutational Analysis | |
dc.subject.mesh | Exons | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Infant | |
dc.subject.mesh | Infant, Newborn | |
dc.subject.mesh | Introns | |
dc.subject.mesh | Phenylketonurias | |
dc.subject.mesh | RNA Splicing | |
dc.subject.mesh | Repressor Proteins | |
dc.subject.mesh | Retrospective Studies | |
dc.subject.mesh | Spain | |
dc.title | Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia. | |
dc.type | research article | |
dc.type.hasVersion | AM | |
dc.volume.number | 41 | |
dspace.entity.type | Publication |