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<p>Pathogenic variants affecting components of the mitochondrial translation machinery lead to various impairments of mitochondrial function and thereby cause a spectrum of multisystem diseases. In an infant with a fatal, metabolic multisystem condition we performed a comprehensive multi-omics approach and detected the intronic biallelic variant NM_014050.4:c.219+6 T &gt; A in <i>MRPL42</i> (mitochondrial ribosomal protein L42) encoding a component of the large mitochondrial ribosomal subunit. RNA-seq revealed a strong reduction and aberrant splicing of the majority of <i>MRPL42</i> transcripts leading to a frameshift and thereby to a premature termination codon: p.(Asn46Leufs*18). However, additional use of the canonical splice site led to a low residual expression of the wildtype transcript and MRPL42 protein abundance was consequently strongly reduced. Complex I and IV activity of the oxidative phosphorylation (OXPHOS) system were reduced and a decrease of complex I, III, IV, and mitoribosomal-related proteins was identified by proteomics. Complementation with wildtype <i>MRPL42</i> corrected most of these phenotypes confirming that they were a direct consequence of the limited availability of MRPL42. Our multi-omics data confirm biallelic <i>MRPL42</i> loss-of-function as the underlying cause of the fatal mitochondrial disease in our patient. Therefore, we propose MRPL42 deficiency as the cause of a mitochondrial ribosome-related combined OXPHOS-deficiency syndrome.</p>

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A biallelic MRPL42 variant causes a combined oxidative phosphorylation deficiency syndrome revealed by multi-omics

  • 期刊论文

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  • 发表日期：

    2026年4月3日

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  • Felix Boschann,
  • Johannes Kopp,
  • Susanne Römer,
  • Oliver Küchler,
  • Hristiana Lyubenova,
  • Nicolai von Kügelgen,
  • Erik Hertstein,
  • Lea Hagelstein,
  • Christian Becker,
  • Kerstin Becker,
  • Sebastian Brachs,
  • Knut Mai,
  • David Meierhofer,
  • Dominik Seelow,
  • Stefan Mundlos,
  • Denise Horn,
  • Markus Schuelke,
  • Björn Fischer-Zirnsak

摘要

Pathogenic variants affecting components of the mitochondrial translation machinery lead to various impairments of mitochondrial function and thereby cause a spectrum of multisystem diseases. In an infant with a fatal, metabolic multisystem condition we performed a comprehensive multi-omics approach and detected the intronic biallelic variant NM_014050.4:c.219+6 T > A in MRPL42 (mitochondrial ribosomal protein L42) encoding a component of the large mitochondrial ribosomal subunit. RNA-seq revealed a strong reduction and aberrant splicing of the majority of MRPL42 transcripts leading to a frameshift and thereby to a premature termination codon: p.(Asn46Leufs*18). However, additional use of the canonical splice site led to a low residual expression of the wildtype transcript and MRPL42 protein abundance was consequently strongly reduced. Complex I and IV activity of the oxidative phosphorylation (OXPHOS) system were reduced and a decrease of complex I, III, IV, and mitoribosomal-related proteins was identified by proteomics. Complementation with wildtype MRPL42 corrected most of these phenotypes confirming that they were a direct consequence of the limited availability of MRPL42. Our multi-omics data confirm biallelic MRPL42 loss-of-function as the underlying cause of the fatal mitochondrial disease in our patient. Therefore, we propose MRPL42 deficiency as the cause of a mitochondrial ribosome-related combined OXPHOS-deficiency syndrome.