Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia
AuthorGallego, Diana; Leal, Fátima; Gámez Abascal, María Alejandra; Castro, Margarita; Navarrete, Rosa; Sanchez-Lijarcio, Obdulia; Vitoria, Isidro; Bueno-Delgado, María; Belanger-Quintana, Amaya; Morais, Ana; Pedrón-Giner, Consuelo; García, Inmaculada; Campistol, Jaume; Artuch, Rafael; Alcaide, Carlos; Cornejo, Veronica; Gil, David; Yahyaoui, Raquel; Ruiz Desviat, Lourdes; Ugarte, Magdalena; Martínez, Aurora; Pérez, Belén
EntityUAM. Departamento de Biología Molecular
10.1002/humu.24026Human Mutation (2020): 25 April
ISSN1059-7794 (print); 1098-1004 (online)
Funded byThis work was funded by grant PI16/00573, B2017/BMD-3721, the Fundación Isabel Gemio and the Fundación La Caixa (LCF/PR/PR16/11110018), an institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa, and the European Regional Development Fund
ProjectGobierno de España. PI16/00573; Comunidad de Madrid. B2017/BMD-3721/RAREGENOMICS
SubjectsDNAJC12; hyperphenylalaninemia; phenylketonuria; molecular chaperones; proteostasis network; Biología y Biomedicina / Biología
NoteThis is the peer reviewed version of the following article: Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia. Human Mutation (2020): 25 April, which has been published in final form at [https://doi.org/10.1002/humu.24026. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
The variants identified in this study are openly available at http://www.lovd.nl/ with reference numbers 0000644164, 0000645396, 0000644166, and 0000405673
Rights© 2020 Wiley Periodicals, Inc.
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
Google Scholar:Gallego, Diana - Leal, Fátima - Gámez Abascal, María Alejandra - Castro, Margarita - Navarrete, Rosa - Sanchez-Lijarcio, Obdulia - Vitoria, Isidro - Bueno-Delgado, María - Belanger-Quintana, Amaya - Morais, Ana - Pedrón-Giner, Consuelo - García, Inmaculada - Campistol, Jaume - Artuch, Rafael - Alcaide, Carlos - Cornejo, Veronica - Gil, David - Yahyaoui, Raquel - Ruiz Desviat, Lourdes - Ugarte, Magdalena - Martínez, Aurora - Pérez, Belén
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