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

Open/ Download
Access note
Acceso a solo metadatos
Publication date
2020Metadata
Show full item record
Cómo citar
Gallego, Diana
Cómo citar
Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia
Author
- Gallego, Diana;
- Leal, Fatima;
- Gámez, Alejandra;
- Castro, Margarita;
- Navarrete, Rosa;
- Sánchez Lijarcio, Obdulia;
- Vitoria, Isidro;
- Bueno Delgado, María;
- Belanger Quintana, Amaya;
- Morais, Ana;
- Pedrón Giner, Consuelo;
- García, Inmaculada;
- Campistol, Jaume;
- Artuch, Rafael;
- Alcaide, Carlos;
- Cornejo Espinoza, Verónica;
- Gil, David;
- Yahyaoui, Raquel;
- Desviat, Lourdes R.;
- Ugarte, Magdalena;
- Martínez, Aurora;
- Pérez, Belén;
Abstract
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.
Patrocinador
Consejería de Educación e Investigación: B2017/BMD-3721. Fundación Isabel Gemio-La Caixa: LCF/PR/PR16/11110018. Ministerio de Ciencia Tecnología y Telecomunicaciones PI16/00573.
Indexation
Artículo de publicación ISI Artículo de publicación SCOPUS
Quote Item
Human Mutation (Apr 2020)
Collections