Genetic defects in mtDNA-encoded protein translation cause pediatric, mitochondrial cardiomyopathy with early-onset brain disease

Rick Kamps, Radek Szklarczyk, Tom E. Theunissen, Debby M. E. I. Hellebrekers, Suzanne C. E. H. Sallevelt, Iris B. Boesten, Bart de Koning, Bianca J. van den Bosch, Gajja S. Salomons, Marisa Simas-Mendes, Rob Verdijk, Kees Schoonderwoerd, Irenaeus F. M. de Coo, Jo M. Vanoevelen, Hubert J. M. Smeets*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

This study aims to identify gene defects in pediatric cardiomyopathy and early-onset brain disease with oxidative phosphorylation (OXPHOS) deficiencies. We applied whole-exome sequencing in three patients with pediatric cardiomyopathy and early-onset brain disease with OXPHOS deficiencies. The brain pathology was studied by MRI analysis. In consanguineous patient 1, we identified a homozygous intronic variant (c.850-3A > G) in the QRSL1 gene, which was predicted to cause abnormal splicing. The variant segregated with the disease and affected the protein function, which was confirmed by complementation studies, restoring OXPHOS function only with wild-type QRSL1. Patient 2 was compound heterozygous for two novel affected and disease-causing variants (c.[253G > A];[938G > A]) in the MTO1 gene. In patient 3, we detected one unknown affected and disease-causing variants (c.2872C > T) and one known disease-causing variant (c.1774C > T) in the AARS2 gene. The c.1774C > T variant was present in the paternal copy of the AARS2 gene, the c.2872C > T in the maternal copy. All genes were involved in translation of mtDNA-encoded proteins. Defects in mtDNA-encoded protein translation lead to severe pediatric cardiomyopathy and brain disease with OXPHOS abnormalities. This suggests that the heart and brain are particularly sensitive to defects in mitochondrial protein synthesis during late embryonic or early postnatal development, probably due to the massive mitochondrial biogenesis occurring at that stage. If both the heart and brain are involved, the prognosis is poor with a likely fatal outcome at young age.
Original languageEnglish
Pages (from-to)537-551
Number of pages15
JournalEuropean Journal of Human Genetics
Volume26
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018

Keywords

  • TRANSFER-RNA-SYNTHETASE
  • EXOME SEQUENCING REVEALS
  • LACTIC-ACIDOSIS
  • HYPERTROPHIC CARDIOMYOPATHY
  • PERIPHERAL NEUROPATHY
  • PERRAULT SYNDROME
  • LEIGH-SYNDROME
  • HEARING-LOSS
  • MUTATIONS
  • DEFICIENCIES

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