A genetic modifier of symptom onset in Pompe disease.

Adolescent Adult Age of Onset Alleles Child Child, Preschool Gene Frequency Genes, Modifier Genetic Association Studies Genetic Predisposition to Disease Genotype Glycogen Storage Disease Type II / diagnosis Humans Infant Introns Middle Aged Mutation Phenotype RNA Splicing Symptom Assessment Young Adult alpha-Glucosidases / genetics
Lysosomal storage disease Modifying factor Pompe disease Pre-mRNA splicing c.510C>T

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
May 2019
Historique:
received: 13 02 2019
revised: 08 03 2019
accepted: 18 03 2019
pubmed: 30 3 2019
medline: 26 11 2019
entrez: 30 3 2019
Statut: ppublish

Résumé

Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1) variant/null (i.e. fully deleterious) acid α-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset. We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays. In compound heterozygous IVS1 patients, the synonymous variant c.510C>T was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c.510C>T than it was in patients without c.510C>T. By reducing the extent of leaky wild-type splicing, c.510C>T modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510C>T was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510C>T variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510C>T caused reduced leaky wild-type splicing. c.510C>T is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. FUND: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17-32) and Metakids (2016-063).

Sections du résumé

BACKGROUND BACKGROUND
Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1) variant/null (i.e. fully deleterious) acid α-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset.
METHODS METHODS
We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays.
FINDINGS RESULTS
In compound heterozygous IVS1 patients, the synonymous variant c.510C>T was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c.510C>T than it was in patients without c.510C>T. By reducing the extent of leaky wild-type splicing, c.510C>T modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510C>T was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510C>T variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510C>T caused reduced leaky wild-type splicing.
INTERPRETATION CONCLUSIONS
c.510C>T is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. FUND: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17-32) and Metakids (2016-063).

Identifiants

DOI: 10.1016/j.ebiom.2019.03.048 PMID: 30922962 PMC: PMC6562017
pubmed: 30922962
pii: S2352-3964(19)30193-8
doi: 10.1016/j.ebiom.2019.03.048
pmc: PMC6562017
pii:
doi:

Substances chimiques

alpha-Glucosidases EC 3.2.1.20

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

553-561

Informations de copyright

Copyright © 2019. Published by Elsevier B.V.

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Auteurs

Atze J Bergsma (AJ)

Department of Pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, Netherlands.

Stijn L M In 't Groen (SLM)

Department of Pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, Netherlands.

Jan J A van den Dorpel (JJA)

Department of Pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, Netherlands.

Hannerieke J M P van den Hout (HJMP)

Department of Pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, Netherlands.

Nadine A M E van der Beek (NAME)

Department of Pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, Netherlands.

Benedikt Schoser (B)

Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.

Antonio Toscano (A)

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Olimpia Musumeci (O)

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Bruno Bembi (B)

Academic Hospital "Santa Maria della Misericordia", Udine, Italy.

Andrea Dardis (A)

Academic Hospital "Santa Maria della Misericordia", Udine, Italy.

Amelia Morrone (A)

Neurofarba, University of Florence, Meyer Children's Hospital, Florence, Italy.

Albina Tummolo (A)

Giovanni XXIII Children's Hospital, Bari, Italy.

Elisabetta Pasquini (E)

Meyer Children's Hospital, Florence, Italy.

Ans T van der Ploeg (AT)

Department of Pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, Netherlands.

W W M Pim Pijnappel (WWMP)

Department of Pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, Netherlands. Electronic address: w.pijnappel@erasmusmc.nl.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Environnement et santé publique › Santé publique › Facteurs épidémiologiques › Facteurs âges › Âge de début › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Allèles › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Enfant d'âge préscolaire › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Phénomènes génétiques › Fréquence d'allèle › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Gènes modificateurs › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Études d'associations génétiques › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Phénomènes génétiques › Génotype › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Erreurs innées du métabolisme › Maladies lysosomiales › Maladies neurologiques de surcharge lysosomiale › Glycogénose de type II › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Personnes › Tranches d'âge › Nourrisson › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Introns › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Phénomènes génétiques › Phénotype › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Épissage des ARN › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Évaluation des symptômes › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Jeune adulte › A genetic modifier of symptom onset in Pompe disease.
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Glycosidases › Glucosidases › alpha-Glucosidase › A genetic modifier of symptom onset in Pompe disease.