Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
G0800674
Medical Research Council - United Kingdom
MR/K000608/1
Medical Research Council - United Kingdom
203105/Z/16/Z
Wellcome Trust - United Kingdom
I 2741
Austrian Science Fund FWF - Austria
0948685/Z/10/Z
Wellcome Trust - United Kingdom
MR/J010448/1
Medical Research Council - United Kingdom
NIHR-HCS-D12-03-04
Department of Health - United Kingdom
Wellcome Trust - United Kingdom
G0601943
Medical Research Council - United Kingdom
PubMed
30245030
PubMed Central
PMC6174280
DOI
10.1016/j.ajhg.2018.08.013
PII: S0002-9297(18)30281-7
Knihovny.cz E-zdroje
- Klíčová slova
- NDUFA6, complex I, complexome profiling, mitochondrial disease,
- MeSH
- alely MeSH
- fenotyp MeSH
- fibroblasty patologie MeSH
- genetická heterogenita MeSH
- kojenec MeSH
- lidé MeSH
- mitochondriální nemoci genetika MeSH
- mitochondriální proteiny genetika MeSH
- mitochondrie genetika MeSH
- mutace genetika MeSH
- respirační komplex I nedostatek genetika MeSH
- sekvence aminokyselin MeSH
- sekvenční seřazení MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- mitochondriální proteiny MeSH
- respirační komplex I MeSH
Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects' fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects' fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ∼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.
Cambridge University Hospitals NHS Foundation Trust Cambridge Biomedical Campus Cambridge CB2 0QQ UK
Cologne Center for Genomics University of Cologne 50931 Cologne Germany
Department of Neuroradiology Oxford University Hospitals NHS Foundation Trust Oxford OX3 9DU UK
Department of Pediatrics Drammen Sykehus 3004 Drammen Norway
Institute of Physiology Czech Academy of Sciences 142 20 Prague Czech Republic
Nuffield Department of Women's and Reproductive Health University of Oxford Oxford OX3 9DU UK
Trevor Mann Baby Unit Brighton and Sussex University Hospitals NHS Trust Brighton BN2 5BE UK
Zobrazit více v PubMed
Formosa L.E., Dibley M.G., Stroud D.A., Ryan M.T. Building a complex complex: Assembly of mitochondrial respiratory chain complex I. Semin. Cell Dev. Biol. 2018;76:154–162. PubMed
Calvo S.E., Clauser K.R., Mootha V.K. MitoCarta2.0: An updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 2016;44(D1):D1251–D1257. PubMed PMC
Frazier A.E., Thorburn D.R., Compton A.G. Mitochondrial energy generation disorders: Genes, mechanisms and clues to pathology. J. Biol. Chem. 2017 Published online December 12, 2017. PubMed PMC
Piekutowska-Abramczuk D., Assouline Z., Mataković L., Feichtinger R.G., Koňařiková E., Jurkiewicz E., Stawiński P., Gusic M., Koller A., Pollak A. NDUFB8 mutations cause mitochondrial complex I deficiency in individuals with Leigh-like encephalomyopathy. Am. J. Hum. Genet. 2018;102:460–467. PubMed PMC
Haack T.B., Kopajtich R., Freisinger P., Wieland T., Rorbach J., Nicholls T.J., Baruffini E., Walther A., Danhauser K., Zimmermann F.A. ELAC2 mutations cause a mitochondrial RNA processing defect associated with hypertrophic cardiomyopathy. Am. J. Hum. Genet. 2013;93:211–223. PubMed PMC
Freisinger P., Haack T., Kopajtich R., Johannes M., Ahting U., Sperl W., Plecko B., Wilichowski E., Meitinger T., Prokisch H. Mitochondriopathy due to mutations in MTFMT: A predominant neurologic phenotype. Neuropediatrics. 2013;44 FV12_03.
Ohtake A., Murayama K., Mori M., Harashima H., Yamazaki T., Tamaru S., Yamashita Y., Kishita Y., Nakachi Y., Kohda M. Diagnosis and molecular basis of mitochondrial respiratory chain disorders: Exome sequencing for disease gene identification. Biochim. Biophys. Acta. 2014;1840:1355–1359. PubMed
Sobreira N., Schiettecatte F., Valle D., Hamosh A. GeneMatcher: A matching tool for connecting investigators with an interest in the same gene. Hum. Mutat. 2015;36:928–930. PubMed PMC
Alston C.L., Howard C., Oláhová M., Hardy S.A., He L., Murray P.G., O’Sullivan S., Doherty G., Shield J.P., Hargreaves I.P. A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype. J. Med. Genet. 2016;53:634–641. PubMed PMC
Ploski R., Pollak A., Müller S., Franaszczyk M., Michalak E., Kosinska J., Stawinski P., Spiewak M., Seggewiss H., Bilinska Z.T. Does p.Q247X in TRIM63 cause human hypertrophic cardiomyopathy? Circ. Res. 2014;114:e2–e5. PubMed
Lunter G., Goodson M. Stampy: A statistical algorithm for sensitive and fast mapping of Illumina sequence reads. Genome Res. 2011;21:936–939. PubMed PMC
Rimmer A., Phan H., Mathieson I., Iqbal Z., Twigg S.R.F., Wilkie A.O.M., McVean G., Lunter G., WGS500 Consortium Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat. Genet. 2014;46:912–918. PubMed PMC
Carss K.J., Arno G., Erwood M., Stephens J., Sanchis-Juan A., Hull S., Megy K., Grozeva D., Dewhurst E., Malka S., NIHR-BioResource Rare Diseases Consortium Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am. J. Hum. Genet. 2017;100:75–90. PubMed PMC
Calabrese C., Simone D., Diroma M.A., Santorsola M., Guttà C., Gasparre G., Picardi E., Pesole G., Attimonelli M. MToolBox: A highly automated pipeline for heteroplasmy annotation and prioritization analysis of human mitochondrial variants in high-throughput sequencing. Bioinformatics. 2014;30:3115–3117. PubMed PMC
Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., Grody W.W., Hegde M., Lyon E., Spector E., ACMG Laboratory Quality Assurance Committee Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015;17:405–424. PubMed PMC
Kircher M., Witten D.M., Jain P., O’Roak B.J., Cooper G.M., Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 2014;46:310–315. PubMed PMC
Lee C., Kalmar L., Xue B., Tompa P., Daughdrill G.W., Uversky V.N., Han K.H. Contribution of proline to the pre-structuring tendency of transient helical secondary structure elements in intrinsically disordered proteins. Biochim. Biophys. Acta. 2014;1840:993–1003. PubMed
Thermann R., Neu-Yilik G., Deters A., Frede U., Wehr K., Hagemeier C., Hentze M.W., Kulozik A.E. Binary specification of nonsense codons by splicing and cytoplasmic translation. EMBO J. 1998;17:3484–3494. PubMed PMC
Kremer L.S., Bader D.M., Mertes C., Kopajtich R., Pichler G., Iuso A., Haack T.B., Graf E., Schwarzmayr T., Terrile C. Genetic diagnosis of Mendelian disorders via RNA sequencing. Nat. Commun. 2017;8:15824. PubMed PMC
Pesta D., Gnaiger E. High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol. Biol. 2012;810:25–58. PubMed
Oláhová M., Hardy S.A., Hall J., Yarham J.W., Haack T.B., Wilson W.C., Alston C.L., He L., Aznauryan E., Brown R.M. LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population. Brain. 2015;138:3503–3519. PubMed PMC
Zerbetto E., Vergani L., Dabbeni-Sala F. Quantification of muscle mitochondrial oxidative phosphorylation enzymes via histochemical staining of blue native polyacrylamide gels. Electrophoresis. 1997;18:2059–2064. PubMed
Neuhoff V., Arold N., Taube D., Ehrhardt W. Improved staining of proteins in polyacrylamide gels including isoelectric focusing gels with clear background at nanogram sensitivity using Coomassie Brilliant Blue G-250 and R-250. Electrophoresis. 1988;9:255–262. PubMed
Stroud D.A., Maher M.J., Lindau C., Vögtle F.N., Frazier A.E., Surgenor E., Mountford H., Singh A.P., Bonas M., Oeljeklaus S. COA6 is a mitochondrial complex IV assembly factor critical for biogenesis of mtDNA-encoded COX2. Hum. Mol. Genet. 2015;24:5404–5415. PubMed
Wirth C., Brandt U., Hunte C., Zickermann V. Structure and function of mitochondrial complex I. Biochim. Biophys. Acta. 2016;1857:902–914. PubMed
Fuhrmann D.C., Wittig I., Dröse S., Schmid T., Dehne N., Brüne B. Degradation of the mitochondrial complex I assembly factor TMEM126B under chronic hypoxia. Cell. Mol. Life Sci. 2018;75:3051–3067. PubMed PMC
Heide H., Bleier L., Steger M., Ackermann J., Dröse S., Schwamb B., Zörnig M., Reichert A.S., Koch I., Wittig I., Brandt U. Complexome profiling identifies TMEM126B as a component of the mitochondrial complex I assembly complex. Cell Metab. 2012;16:538–549. PubMed
Angerer H., Radermacher M., Mańkowska M., Steger M., Zwicker K., Heide H., Wittig I., Brandt U., Zickermann V. The LYR protein subunit NB4M/NDUFA6 of mitochondrial complex I anchors an acyl carrier protein and is essential for catalytic activity. Proc. Natl. Acad. Sci. USA. 2014;111:5207–5212. PubMed PMC
Ogilvie I., Kennaway N.G., Shoubridge E.A. A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. J. Clin. Invest. 2005;115:2784–2792. PubMed PMC
Mckenzie M., Ryan M.T. Assembly factors of human mitochondrial complex I and their defects in disease. IUBMB Life. 2010;62:497–502. PubMed
Lazarou M., McKenzie M., Ohtake A., Thorburn D.R., Ryan M.T. Analysis of the assembly profiles for mitochondrial- and nuclear-DNA-encoded subunits into complex I. Mol. Cell. Biol. 2007;27:4228–4237. PubMed PMC
Stroud D.A., Surgenor E.E., Formosa L.E., Reljic B., Frazier A.E., Dibley M.G., Osellame L.D., Stait T., Beilharz T.H., Thorburn D.R. Accessory subunits are integral for assembly and function of human mitochondrial complex I. Nature. 2016;538:123–126. PubMed
Wu M., Gu J., Guo R., Huang Y., Yang M. Structure of mammalian respiratory supercomplex I1III2IV1. Cell. 2016;167:1598–1609.e10. PubMed
Alston C.L., Compton A.G., Formosa L.E., Strecker V., Oláhová M., Haack T.B., Smet J., Stouffs K., Diakumis P., Ciara E. Biallelic mutations in TMEM126B cause severe complex I deficiency with a variable clinical phenotype. Am. J. Hum. Genet. 2016;99:217–227. PubMed PMC
Sánchez-Caballero L., Ruzzenente B., Bianchi L., Assouline Z., Barcia G., Metodiev M.D., Rio M., Funalot B., van den Brand M.A., Guerrero-Castillo S. Mutations in complex I assembly factor TMEM126B result in muscle weakness and isolated complex I deficiency. Am. J. Hum. Genet. 2016;99:208–216. PubMed PMC
Punzi G., Porcelli V., Ruggiu M., Hossain M.F., Menga A., Scarcia P., Castegna A., Gorgoglione R., Pierri C.L., Laera L. SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency. Hum. Mol. Genet. 2018;27:499–504. PubMed PMC
Schottmann G., Picker-Minh S., Schwarz J.M., Gill E., Rodenburg R.J.T., Stenzel W., Kaindl A.M., Schuelke M. Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia. Mitochondrion. 2017;37:46–54. PubMed
Haack T.B., Haberberger B., Frisch E.M., Wieland T., Iuso A., Gorza M., Strecker V., Graf E., Mayr J.A., Herberg U. Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. J. Med. Genet. 2012;49:277–283. PubMed
Swalwell H., Kirby D.M., Blakely E.L., Mitchell A., Salemi R., Sugiana C., Compton A.G., Tucker E.J., Ke B.X., Lamont P.J. Respiratory chain complex I deficiency caused by mitochondrial DNA mutations. Eur. J. Hum. Genet. 2011;19:769–775. PubMed PMC