RT Journal Article T1 Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia. A1 Gallego, Diana A1 Leal, Fátima A1 Gámez, Alejandra A1 Castro, Margarita A1 Navarrete, Rosa A1 Sanchez-Lijarcio, Obdulia A1 Vitoria, Isidro A1 Bueno-Delgado, María A1 Belanger-Quintana, Amaya A1 Morais, Ana A1 Pedrón-Giner, Consuelo A1 García, Inmaculada A1 Campistol, Jaume A1 Artuch, Rafael A1 Alcaide, Carlos A1 Cornejo, Veronica A1 Gil, David A1 Yahyaoui, Raquel A1 Desviat, Lourdes R A1 Ugarte, Magdalena A1 Martínez, Aurora A1 Pérez, Belén K1 DNAJC12 K1 hyperphenylalaninemia K1 molecular chaperones K1 phenylketonuria K1 proteostasis network AB 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. YR 2020 FD 2020-04-30 LK http://hdl.handle.net/10668/15431 UL http://hdl.handle.net/10668/15431 LA en DS RISalud RD Feb 18, 2025