Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies

Thatjana Gardeitchik; Miski Mohamed; Benedetta Ruzzenente; Daniela Karall; Sergio Guerrero-Castillo; Daisy Dalloyaux; Mariël van den Brand; Sanne van Kraaij; Ellyze van Asbeck; Zahra Assouline; Marlene Rio; Pascale de Lonlay; Sabine Scholl-Buergi; David F G J Wolthuis; Alexander Hoischen; Richard J Rodenburg; Wolfgang Sperl; Zsolt Urban; Ulrich Brandt; Johannes A Mayr; Sunnie Wong; Arjan P M de Brouwer; Leo Nijtmans; Arnold Munnich; Agnès Rötig; Ron A Wevers; Metodi D Metodiev; Eva Morava

doi:10.1016/j.ajhg.2018.02.012

Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies

Am J Hum Genet. 2018 Apr 5;102(4):685-695. doi: 10.1016/j.ajhg.2018.02.012. Epub 2018 Mar 22.

Authors

Thatjana Gardeitchik¹, Miski Mohamed², Benedetta Ruzzenente³, Daniela Karall⁴, Sergio Guerrero-Castillo⁵, Daisy Dalloyaux², Mariël van den Brand⁶, Sanne van Kraaij⁷, Ellyze van Asbeck², Zahra Assouline⁸, Marlene Rio⁸, Pascale de Lonlay⁹, Sabine Scholl-Buergi⁴, David F G J Wolthuis², Alexander Hoischen¹⁰, Richard J Rodenburg¹¹, Wolfgang Sperl⁴, Zsolt Urban¹², Ulrich Brandt⁵, Johannes A Mayr¹³, Sunnie Wong¹⁴, Arjan P M de Brouwer¹⁵, Leo Nijtmans⁶, Arnold Munnich¹⁶, Agnès Rötig³, Ron A Wevers¹⁷, Metodi D Metodiev¹⁸, Eva Morava¹⁹

Affiliations

¹ Department of Pediatrics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
² Department of Pediatrics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
³ INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
⁴ Clinic for Pediatrics, Inherited Metabolic Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria.
⁵ Department of Pediatrics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Medical Center, 6500 HB Nijmegen, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
⁶ Department of Pediatrics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Medical Center, 6500 HB Nijmegen, the Netherlands.
⁷ Department of Pediatrics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
⁸ Departments of Pediatrics, Neurology, and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France.
⁹ Reference Center for Inherited Metabolic Diseases, Hôpital Necker-Enfants-Malades, Assistance Publique - Hôpitaux de Paris, Université Paris Descartes, Institut Imagine, 75015 Paris, France.
¹⁰ Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
¹¹ Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Medical Center, 6500 HB Nijmegen, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
¹² Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA.
¹³ Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
¹⁴ Hayward Genetics Center, Tulane University, LA 70112, USA.
¹⁵ Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Medical Center, 6500 HB Nijmegen, the Netherlands.
¹⁶ INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France; Departments of Pediatrics, Neurology, and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France.
¹⁷ Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
¹⁸ INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France. Electronic address: metodi.metodiev@inserm.fr.
¹⁹ Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: emoravakozicz@tulane.edu.

Abstract

Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Using exome sequencing in two unrelated subjects presenting with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency, we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease. Characterization of subjects' fibroblasts revealed a decrease in the steady-state amounts of mutant MRPS2, and this decrease was shown by complexome profiling to prevent the assembly of the small mitoribosomal subunit. In turn, mitochondrial translation was inhibited, resulting in a combined OXPHOS deficiency detectable in subjects' muscle and liver biopsies as well as in cultured skin fibroblasts. Reintroduction of wild-type MRPS2 restored mitochondrial translation and OXPHOS assembly. The combination of lactic acidemia, hypoglycemia, and sensorineural hearing loss, especially in the presence of a combined OXPHOS deficiency, should raise suspicion for a ribosomal-subunit-related mitochondrial defect, and clinical recognition could allow for a targeted diagnostic approach. The identification of MRPS2 as an additional gene related to mitochondrial disease further expands the genetic and phenotypic spectra of OXPHOS deficiencies caused by impaired mitochondrial translation.

Keywords: 2-oxoglutaric acid; combined OXPHOS complex deficiencies; complexome profiling; hearing loss; mitochondrial ribosomes; mitochondrial translation defect; wrinkly skin.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Alleles*
Amino Acid Sequence
Child, Preschool
DNA Mutational Analysis
DNA, Mitochondrial / genetics
Female
Fibroblasts / metabolism
Hearing Loss, Sensorineural / complications
Hearing Loss, Sensorineural / genetics*
Humans
Hypoglycemia / complications
Hypoglycemia / genetics*
Infant
Infant, Newborn
Male
Mitochondrial Diseases / complications
Mitochondrial Diseases / genetics*
Mitochondrial Proteins / chemistry
Mitochondrial Proteins / genetics*
Mutation / genetics*
Oxidative Phosphorylation
Protein Subunits / genetics
RNA, Ribosomal / genetics
Ribosomal Proteins / chemistry
Ribosomal Proteins / genetics*

Substances

DNA, Mitochondrial
MRPS2 protein, human
Mitochondrial Proteins
Protein Subunits
RNA, Ribosomal
Ribosomal Proteins

Grants and funding

R01 HL090648/HL/NHLBI NIH HHS/United States