%0 Journal Article %A Gallego, Diana %A Leal, Fátima %A Gámez, Alejandra %A Castro, Margarita %A Navarrete, Rosa %A Sanchez-Lijarcio, Obdulia %A Vitoria, Isidro %A Bueno-Delgado, María %A Belanger-Quintana, Amaya %A Morais, Ana %A Pedrón-Giner, Consuelo %A García, Inmaculada %A Campistol, Jaume %A Artuch, Rafael %A Alcaide, Carlos %A Cornejo, Veronica %A Gil, David %A Yahyaoui, Raquel %A Desviat, Lourdes R %A Ugarte, Magdalena %A Martínez, Aurora %A Pérez, Belén %T Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia. %D 2020 %U http://hdl.handle.net/10668/15431 %X 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. %K DNAJC12 %K hyperphenylalaninemia %K molecular chaperones %K phenylketonuria %K proteostasis network %~