MRPS25 mutations impair mitochondrial translation and cause encephalomyopathy
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Abstract
Mitochondrial disorders are clinically and genetically heterogeneous, and are associated with a
variety of disease mechanisms. Defects of mitochondrial protein synthesis account for the largest
subgroup of disorders manifesting with impaired respiratory chain capacity; yet, only a few have
been linked to dysfunction in the protein components of the mitochondrial ribosomes. Here, we
report a subject presenting with dyskinetic cerebral palsy and partial agenesis of the corpus
callosum, while histochemical and biochemical analyses of skeletal muscle revealed signs of
mitochondrial myopathy. Using exome sequencing, we identified a homozygous variant,
c.215C>T, in MRPS25, which encodes for a structural component of the 28S small subunit of the
mitochondrial ribosome (mS25). The variant segregates with the disease, and substitutes a highly
conserved proline residue with leucine (p.P72L) that, based on the high resolution structure of the
28S ribosome, is predicted to compromise inter-protein contacts and destabilize the small subunit.
Concordant with the in silico analysis, patient’s fibroblasts showed decreased levels of MRPS25
and other components of the 28S subunit. Moreover, mutant fibroblasts showed a dearth of the
28S assembly accompanied by impaired mitochondrial translation and decreased levels of
multiple respiratory chain subunits. Crucially, these abnormalities were rescued by transgenic
expression of wild-type MRPS25 in the mutant fibroblasts. Collectively, our data demonstrate the
pathogenicity of the p.P72L variant, and identified MRPS25 as a new cause of mitochondrial
translation defect