Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia
Por:
Gallego D, Leal F, Gámez A, Castro M, Navarrete R, Sanchez-Lijarcio O, Vitoria I, Bueno-Delgado M, Belanger-Quintana A, Morais A, Pedrón-Giner C, García I, Campistol-Plana J, Artuch-Iriberri R, Alcaide C, Cornejo V, Gil D, Yahyaoui R, Desviat LR, Ugarte M, Martínez A and Pérez B
Publicada:
1 jul 2020
Ahead of Print:
1 abr 2020
Resumen:
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.
Filiaciones:
Gallego D:
Centro de Diagnóstico de Enfermedades Metabólicas, Centro de Biología Molecular, Universidad Autónoma de Madrid, Madrid. CIBERER, IdiPAZ, Spain
Leal F:
Centro de Diagnóstico de Enfermedades Metabólicas, Centro de Biología Molecular, Universidad Autónoma de Madrid, Madrid. CIBERER, IdiPAZ, Spain
Gámez A:
Centro de Diagnóstico de Enfermedades Metabólicas, Centro de Biología Molecular, Universidad Autónoma de Madrid, Madrid. CIBERER, IdiPAZ, Spain
Castro M:
Centro de Diagnóstico de Enfermedades Metabólicas, Centro de Biología Molecular, Universidad Autónoma de Madrid, Madrid. CIBERER, IdiPAZ, Spain
Navarrete R:
Centro de Diagnóstico de Enfermedades Metabólicas, Centro de Biología Molecular, Universidad Autónoma de Madrid, Madrid. CIBERER, IdiPAZ, Spain
Sanchez-Lijarcio O:
Centro de Diagnóstico de Enfermedades Metabólicas, Centro de Biología Molecular, Universidad Autónoma de Madrid, Madrid. CIBERER, IdiPAZ, Spain
Vitoria I:
Hospital Universitario La Fe, Valencia, Spain
Bueno-Delgado M:
Hospital Virgen del Rocío, Seville, Spain
Belanger-Quintana A:
Hospital Universitario Ramón y Cajal, Madrid, Spain
Morais A:
Hospital Universitario La Paz, Madrid, Spain
Pedrón-Giner C:
Hospital Infantil Universitario Niño Jesús, Madrid, Spain
García I:
Hospital Universitario Miguel Servet, Zaragoza, Spain
Campistol-Plana J:
Institut de Recerca and Hospital Universitario Sant Joan de Déu, Barcelona, CIBERER, Spain
Artuch-Iriberri R:
Institut de Recerca and Hospital Universitario Sant Joan de Déu, Barcelona, CIBERER, Spain
Alcaide C:
Hospital Universitario Río Hortega, Valladolid, Spain
Cornejo V:
INTA, Santiago de Chile, Chile
Gil D:
Hospital Virgen de la Arrixaca, Murcia, Spain
Yahyaoui R:
Hospital Regional Universitario de Málaga
Instituto de Investigación Biomédica de Málaga-IBIMA, Spain
Desviat LR:
Centro de Diagnóstico de Enfermedades Metabólicas, Centro de Biología Molecular, Universidad Autónoma de Madrid, Madrid. CIBERER, IdiPAZ, Spain
Ugarte M:
Centro de Diagnóstico de Enfermedades Metabólicas, Centro de Biología Molecular, Universidad Autónoma de Madrid, Madrid. CIBERER, IdiPAZ, Spain
Martínez A:
Department of Biomedicine, University of Bergen, 5009, Bergen, Norway
Pérez B:
Centro de Diagnóstico de Enfermedades Metabólicas, Centro de Biología Molecular, Universidad Autónoma de Madrid, Madrid. CIBERER, IdiPAZ, Spain
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