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

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2020
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Gallego, Diana
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Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia
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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.
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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.
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URI: https://repositorio.uchile.cl/handle/2250/175368
DOI: 10.1002/humu.24026
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Human Mutation (Apr 2020)
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