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

2020; Wiley; Volume: 41; Issue: 7 Linguagem: Inglês

10.1002/humu.24026

1098-1004

Diana Gallego, Fátima Leal, Alejandra Gámez, Margarita Castro, Rosa Navarrete, Obdulia Sánchez‐Lijarcio, Isidro Vitoria, María Amor Bueno-Delgado, Amaya Bélanger-Quintana, Ana Heloneida de Araújo Morais, Consuelo Pedrón‐Giner, Inmaculada García, Jaume Campistol, Rafael Artuch, Carlos Alcaide, Verónica Cornejo, David Gil, Raquel Yahyaoui, Lourdes R. Desviat, Magdalena Ugarte, Aurora Martı́nez, Belén Pérez,

Metabolomics and Mass Spectrometry Studies

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.