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

被引：83

作者：

Lake, Nicole J. ^{[1
,2
]}

Webb, Bryn D. ^{[3
,4
,5
]}

Stroud, David A. ^{[6
]}

Richman, Tara R. ^{[7
,8
]}

Ruzzenente, Benedetta ^{[9
]}

Compton, Alison G. ^{[1
,2
]}

Mountford, Hayley S. ^{[1
,2
,10
]}

Pulman, Juliette ^{[9
]}

Zangarelli, Coralie ^{[9
]}

Rio, Marlene ^{[11
]}

Bodaert, Nathalie ^{[12
,13
]}

Assouline, Zahra ^{[11
]}

Sherpa, Mingma D. ^{[3
,5
]}

Schadt, Eric E. ^{[3
,5
]}

Houten, Sander M. ^{[3
,5
]}

Byrnes, James ^{[14
]}

McCormick, Elizabeth M. ^{[14
]}

Zolkipli-Cunningham, Zarazuela ^{[14
,15
]}

Haude, Katrina ^{[16
]}

Zhang, Zhancheng ^{[16
]}

Retterer, Kyle ^{[16
]}

Bai, Renkui ^{[16
]}

Calvo, Sarah E. ^{[17
,18
,19
]}

Mootha, Vamsi K. ^{[17
,18
,19
]}

Christodoulou, John ^{[1
,2
]}

Rotig, Agnes ^{[9
]}

Filipovska, Aleksandra ^{[7
,8
,20
]}

Cristian, Ingrid ^{[21
,22
]}

Falk, Marni J. ^{[14
,23
]}

Metodiev, Metodi D. ^{[9
]}

Thorburn, David R. ^{[1
,2
,24
]}

机构：

[1] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic 3052, Australia

[2] Univ Melbourne, Dept Paediat, Melbourne, Vic 3052, Australia

[3] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA

[5] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA

[6] Monash Univ, Monash Biomed Discovery Inst, Dept Biochem & Mol Biol, Clayton Campus, Melbourne, Vic 3800, Australia

[7] Univ Western Australia, Harry Perkins Inst Med Res, Nedlands, WA 6009, Australia

[8] Univ Western Australia, Ctr Med Res, Nedlands, WA 6009, Australia

[9] Univ Paris 05, INSERM, U1163, Inst Imaginem,Sorbonne Paris Cite, F-75015 Paris, France

[10] Oxford Brookes Univ, Fac Hlth Sci, Dept Biol & Med Sci, Oxford OX3 0BP, England

[11] Hop Necker Enfants Malad, Dept Pediat Neurol & Genet, F-75015 Paris, France

[12] Univ Paris 05, Hop Necker Enfants Malad, Pediat Radiol Dept,INSERM U1000, AP HP,PRES Sorbonne Paris Cite, F-75015 Paris, France

[13] UMR 1163, Inst Imagine, F-75015 Paris, France

[14] Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA

[15] Childrens Hosp Philadelphia, Dept Pediat, Div Neurol, Philadelphia, PA 19104 USA

[16] GeneDx, Gaithersburg, MD 20877 USA

[17] Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA

[18] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

[19] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[20] Univ Western Australia, Sch Mol Sci, Crawley, WA 6009, Australia

[21] Nemours Childrens Hosp, Orlando, FL 32827 USA

[22] Amold Palmer Hosp Children, Div Genet, Orlando, FL 32806 USA

[23] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[24] Royal Childrens Hosp, Victorian Clin Genet Serv, Melbourne, Vic 3052, Australia

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2017年 / 101卷 / 02期

基金：

澳大利亚研究理事会; 英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

MITOCHONDRIAL TRANSLATION; COMPUTATIONAL PLATFORM; CHAIN COMPLEXES; FRAMEWORK; VARIANT; DISEASE; MRPL44;

D O I：

10.1016/j.ajhg.2017.07.005

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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.

引用

页码：239 / 254

页数：16

共 58 条

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