Gallego, DianaLeal, FátimaGámez, AlejandraCastro, MargaritaNavarrete, RosaSanchez-Lijarcio, ObduliaVitoria, IsidroBueno-Delgado, MaríaBelanger-Quintana, AmayaMorais, AnaPedrón-Giner, ConsueloGarcía, InmaculadaCampistol, JaumeArtuch, RafaelAlcaide, CarlosCornejo, VeronicaGil, DavidYahyaoui, RaquelDesviat, Lourdes RUgarte, MagdalenaMartínez, AuroraPérez, Belén2023-02-082023-02-082020-04-30http://hdl.handle.net/10668/15431Biallelic 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.enDNAJC12hyperphenylalaninemiamolecular chaperonesphenylketonuriaproteostasis networkAdolescentAdultAllelesChildChild, PreschoolDNA Mutational AnalysisExonsHumansInfantInfant, NewbornIntronsPhenylketonuriasRNA SplicingRepressor ProteinsRetrospective StudiesSpainresearch article32333439open access10.1002/humu.240261098-1004https://repositorio.uam.es/bitstream/10486/690974/1/pathogenic_gallego_HM_2020ps.pdf