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MRPS22 variants alter mitochondrial ribosome assembly in patients with leukodystrophy, movement disorder and intellectual impairment

Glasgow, Ruth I.C. ; Lennartsson, Finn LU orcid ; Arnardottir, Snjolaug ; Shiriaev, Dmitrii Igorevich ; Correia, Sandrina P. ; Moedas, Marco ; Peña-Pérez, Lucía ; Paucar, Martin ; Naess, Karin and Bruhn, Helene , et al. (2026) In Human Molecular Genetics 35(10).
Abstract

Mitochondrial diseases are clinically and genetically heterogeneous, often complicating diagnosis. Here, we describe four unrelated individuals with suspected mitochondrial disease who shared similar neuroimaging features, including bilateral symmetrical supra- and infratentorial white-matter abnormalities, together with variable movement disorders and intellectual impairment. Whole-genome sequencing identified the same homozygous MRPS22 variant (c.798_799delinsTA) in all four patients. MRPS22 encodes a component of the mitochondrial small ribosomal subunit (mtSSU). Functional studies in patient-derived fibroblasts showed impaired mitoribosome assembly and reduced de novo mitochondrial translation. Despite largely preserved steady-state... (More)

Mitochondrial diseases are clinically and genetically heterogeneous, often complicating diagnosis. Here, we describe four unrelated individuals with suspected mitochondrial disease who shared similar neuroimaging features, including bilateral symmetrical supra- and infratentorial white-matter abnormalities, together with variable movement disorders and intellectual impairment. Whole-genome sequencing identified the same homozygous MRPS22 variant (c.798_799delinsTA) in all four patients. MRPS22 encodes a component of the mitochondrial small ribosomal subunit (mtSSU). Functional studies in patient-derived fibroblasts showed impaired mitoribosome assembly and reduced de novo mitochondrial translation. Despite largely preserved steady-state levels of OXPHOS proteins, respiratory chain analysis identified a mild, isolated complex I deficiency. Proteomic profiling revealed reduced levels of mitochondrial ribosomal proteins and dysregulation of mitochondrial translation pathways. In line with the proteomic findings, RNA sequencing of fibroblasts from three patients revealed a distinct transcriptional signature compared with controls, with mitochondrial translation emerging as the most affected pathway. Mitochondrial-encoded transcripts were decreased, whereas nuclear-encoded mitochondrial genes were generally increased. Structural modelling suggested that the variant disrupts key interactions important for mitoribosome stability. While previously reported MRPS22 variants have been associated with severe, often prenatal-onset disease, the individuals described here exhibited a milder phenotype, thereby expanding the clinical spectrum of MRPS22-related disorders. Together, these findings support the pathogenicity of this variant and highlight the value of integrated genomic and functional analyses in diagnosing mitochondrial disease.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
adult-onset, mitochondrial ribosome, MRPS22, mS22, translation
in
Human Molecular Genetics
volume
35
issue
10
article number
ddag042
publisher
Oxford University Press
external identifiers
  • pmid:42234462
  • scopus:105041094535
ISSN
0964-6906
DOI
10.1093/hmg/ddag042
language
English
LU publication?
yes
id
201339d1-a589-42c1-b230-6177dc502b2f
date added to LUP
2026-09-21 14:20:02
date last changed
2026-10-06 12:30:35
@article{201339d1-a589-42c1-b230-6177dc502b2f,
  abstract     = {{<p>Mitochondrial diseases are clinically and genetically heterogeneous, often complicating diagnosis. Here, we describe four unrelated individuals with suspected mitochondrial disease who shared similar neuroimaging features, including bilateral symmetrical supra- and infratentorial white-matter abnormalities, together with variable movement disorders and intellectual impairment. Whole-genome sequencing identified the same homozygous MRPS22 variant (c.798_799delinsTA) in all four patients. MRPS22 encodes a component of the mitochondrial small ribosomal subunit (mtSSU). Functional studies in patient-derived fibroblasts showed impaired mitoribosome assembly and reduced de novo mitochondrial translation. Despite largely preserved steady-state levels of OXPHOS proteins, respiratory chain analysis identified a mild, isolated complex I deficiency. Proteomic profiling revealed reduced levels of mitochondrial ribosomal proteins and dysregulation of mitochondrial translation pathways. In line with the proteomic findings, RNA sequencing of fibroblasts from three patients revealed a distinct transcriptional signature compared with controls, with mitochondrial translation emerging as the most affected pathway. Mitochondrial-encoded transcripts were decreased, whereas nuclear-encoded mitochondrial genes were generally increased. Structural modelling suggested that the variant disrupts key interactions important for mitoribosome stability. While previously reported MRPS22 variants have been associated with severe, often prenatal-onset disease, the individuals described here exhibited a milder phenotype, thereby expanding the clinical spectrum of MRPS22-related disorders. Together, these findings support the pathogenicity of this variant and highlight the value of integrated genomic and functional analyses in diagnosing mitochondrial disease.</p>}},
  author       = {{Glasgow, Ruth I.C. and Lennartsson, Finn and Arnardottir, Snjolaug and Shiriaev, Dmitrii Igorevich and Correia, Sandrina P. and Moedas, Marco and Peña-Pérez, Lucía and Paucar, Martin and Naess, Karin and Bruhn, Helene and Lesko, Nicole and Wibom, Rolf and Rorbach, Joanna and Freyer, Christoph and Wedell, Anna and Ygberg, Sofia and Eklund, Erik A. and Wredenberg, Anna}},
  issn         = {{0964-6906}},
  keywords     = {{adult-onset; mitochondrial ribosome; MRPS22; mS22; translation}},
  language     = {{eng}},
  number       = {{10}},
  publisher    = {{Oxford University Press}},
  series       = {{Human Molecular Genetics}},
  title        = {{MRPS22 variants alter mitochondrial ribosome assembly in patients with leukodystrophy, movement disorder and intellectual impairment}},
  url          = {{http://dx.doi.org/10.1093/hmg/ddag042}},
  doi          = {{10.1093/hmg/ddag042}},
  volume       = {{35}},
  year         = {{2026}},
}