Universität zu Köln

Bugiardini, Enrico, Mitchell, Alice L., Dalla Rosa, Ilaria ORCID: 0000-0003-4801-2396, Horning-Do, Hue-Tran, Pitmann, Alan M., Poole, Olivia, V, Holton, Janice L., Shah, Sachit, Woodward, Cathy, Hargreaves, Iain, Quinlivan, Rosaline, Amunts, Alexey, Wiesner, Rudolf J., Houlden, Henry, Holt, Ian J., Hanna, Michael G., Pitceathly, Robert D. S. and Spinazzola, Antonella ORCID: 0000-0003-4242-8091 (2019). MRPS25 mutations impair mitochondrial translation and cause encephalomyopathy. Hum. Mol. Genet., 28 (16). S. 2711 - 2720. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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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 segregated 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, assembled 28S subunits were scarce in the fibroblasts with mutant mS25 leading to 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 identify MRPS25 mutations as a new cause of mitochondrial translation defect.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bugiardini, Enrico UNSPECIFIED UNSPECIFIED UNSPECIFIED Mitchell, Alice L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dalla Rosa, Ilaria UNSPECIFIED orcid.org/0000-0003-4801-2396 UNSPECIFIED Horning-Do, Hue-Tran UNSPECIFIED UNSPECIFIED UNSPECIFIED Pitmann, Alan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Poole, Olivia, V UNSPECIFIED UNSPECIFIED UNSPECIFIED Holton, Janice L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Shah, Sachit UNSPECIFIED UNSPECIFIED UNSPECIFIED Woodward, Cathy UNSPECIFIED UNSPECIFIED UNSPECIFIED Hargreaves, Iain UNSPECIFIED UNSPECIFIED UNSPECIFIED Quinlivan, Rosaline UNSPECIFIED UNSPECIFIED UNSPECIFIED Amunts, Alexey UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiesner, Rudolf J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Houlden, Henry UNSPECIFIED UNSPECIFIED UNSPECIFIED Holt, Ian J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hanna, Michael G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pitceathly, Robert D. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Spinazzola, Antonella UNSPECIFIED orcid.org/0000-0003-4242-8091 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-144238
DOI:	10.1093/hmg/ddz093
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	28
Number:	16
Page Range:	S. 2711 - 2720
Date:	2019
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RIBOSOME; SUBUNIT Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14423