Publication:
Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia.

dc.contributor.authorGallego, Diana
dc.contributor.authorLeal, Fátima
dc.contributor.authorGámez, Alejandra
dc.contributor.authorCastro, Margarita
dc.contributor.authorNavarrete, Rosa
dc.contributor.authorSanchez-Lijarcio, Obdulia
dc.contributor.authorVitoria, Isidro
dc.contributor.authorBueno-Delgado, María
dc.contributor.authorBelanger-Quintana, Amaya
dc.contributor.authorMorais, Ana
dc.contributor.authorPedrón-Giner, Consuelo
dc.contributor.authorGarcía, Inmaculada
dc.contributor.authorCampistol, Jaume
dc.contributor.authorArtuch, Rafael
dc.contributor.authorAlcaide, Carlos
dc.contributor.authorCornejo, Veronica
dc.contributor.authorGil, David
dc.contributor.authorYahyaoui, Raquel
dc.contributor.authorDesviat, Lourdes R
dc.contributor.authorUgarte, Magdalena
dc.contributor.authorMartínez, Aurora
dc.contributor.authorPérez, Belén
dc.date.accessioned2023-02-08T14:47:12Z
dc.date.available2023-02-08T14:47:12Z
dc.date.issued2020-04-30
dc.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.
dc.identifier.doi10.1002/humu.24026
dc.identifier.essn1098-1004
dc.identifier.pmid32333439
dc.identifier.unpaywallURLhttps://repositorio.uam.es/bitstream/10486/690974/1/pathogenic_gallego_HM_2020ps.pdf
dc.identifier.urihttp://hdl.handle.net/10668/15431
dc.issue.number7
dc.journal.titleHuman mutation
dc.journal.titleabbreviationHum Mutat
dc.language.isoen
dc.organizationHospital Universitario Regional de Málaga
dc.organizationInstituto de Investigación Biomédica de Málaga-IBIMA
dc.organizationHospital Universitario Virgen del Rocío
dc.page.number1329-1338
dc.pubmedtypeJournal Article
dc.pubmedtypeResearch Support, Non-U.S. Gov't
dc.rights.accessRightsopen access
dc.subjectDNAJC12
dc.subjecthyperphenylalaninemia
dc.subjectmolecular chaperones
dc.subjectphenylketonuria
dc.subjectproteostasis network
dc.subject.meshAdolescent
dc.subject.meshAdult
dc.subject.meshAlleles
dc.subject.meshChild
dc.subject.meshChild, Preschool
dc.subject.meshDNA Mutational Analysis
dc.subject.meshExons
dc.subject.meshHumans
dc.subject.meshInfant
dc.subject.meshInfant, Newborn
dc.subject.meshIntrons
dc.subject.meshPhenylketonurias
dc.subject.meshRNA Splicing
dc.subject.meshRepressor Proteins
dc.subject.meshRetrospective Studies
dc.subject.meshSpain
dc.titlePathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia.
dc.typeresearch article
dc.type.hasVersionAM
dc.volume.number41
dspace.entity.typePublication

Files