Journal Article


Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Abstract

The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease. Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects. Whole-exome sequencing was used to independently identify all variants. Two splice-site mutations were identified, including homozygous c.321+1G>T in a subject of Italian ancestry and homozygous c.322−10G>A in affected sibling pairs from two unrelated families of Puerto Rican descent. In addition, compound heterozygous MRPS34 mutations were identified in a proband of French ancestry; a missense (c.37G>A [p.Glu13Lys]) and a nonsense (c.94C>T [p.Gln32∗]) variant. We demonstrated that these mutations reduce MRPS34 protein levels and the synthesis of OXPHOS subunits encoded by mtDNA. Examination of the mitoribosome profile and quantitative proteomics showed that the mitochondrial translation defect was caused by destabilization of the small mitoribosomal subunit and impaired monosome assembly. Lentiviral-mediated expression of wild-type MRPS34 rescued the defect in mitochondrial translation observed in skin fibroblasts from affected subjects, confirming the pathogenicity of MRPS34 mutations. Our data establish that MRPS34 is required for normal function of the mitoribosome in humans and furthermore demonstrate the power of quantitative proteomic analysis to identify signatures of defects in specific cellular pathways in fibroblasts from subjects with inherited disease.

Attached files

Authors

Lake, Nicole J.
Webb, Bryn D.
Stroud, David A.
Richman, Tara R.
Ruzzenente, Benedetta
Compton, Alison G.
Mountford, Hayley S.
Pulman, Juliette
Zangarelli, Coralie
Rio, Marelene
Bodaert, Nathalie
Assouline, Zahra
Sherpa, Mingma D.
Schadt, Eric E.
Houten, Sander M.
Byrnes, James
McCormick, Elizabeth M.
Zolkipli-Cunningham, Zarazuela
Haude, Katrina
Zhang, Zhancheng
Retterer, Kyle
Bai, Renkui
Calvo, Sarah E.
Mootha, Vamsi K.
Christodoulou, John
Rötig, Agnes
Filipovska, Aleksandra
Cristian, Ingrid
Falk, Marni J.
Metodiev, Metodi D.
Thorburn, David R.

Oxford Brookes departments

Faculty of Health and Life Sciences\Department of Biological and Medical Sciences

Dates

Year of publication: 2017
Date of RADAR deposit: 2017-08-24


Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License


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