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

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.

• Authors: Diana Gallego, Fátima Leal, Alejandra Gámez, Margarita Castro, Rosa Navarrete, Obdulia Sanchez-Lijarcio, Isidro Vitoria, María Bueno-Delgado, Amaya Belanger-Quintana, Ana Morais, Consuelo Pedrón-Giner, Inmaculada García, Jaume Campistol, Rafael Artuch, Carlos Alcaide, Veronica Cornejo, David Gil, Raquel Yahyaoui, Lourdes R Desviat, Magdalena Ugarte, Aurora Martínez, Belén Pérez
• Journal: Human mutation (Hum Mutat) Vol. 41 Issue 7 Pg. 1329-1338 (07 2020) ISSN: 1098-1004 [Electronic] United States
• PMID: 32333439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley Periodicals, Inc.

Chemical References

• DNAJC12 protein, human
• Repressor Proteins

Topics

• Adolescent
• Adult
• Alleles
• Child
• Child, Preschool
• DNA Mutational Analysis
• Exons
• Humans
• Infant
• Infant, Newborn
• Introns
• Phenylketonurias (genetics)
• RNA Splicing
• Repressor Proteins (genetics)
• Retrospective Studies
• Spain