Recent Advances in Understanding the Molecular Genetic Basis of Mitochondrial Disease
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Received: 21 January 2019 Revised: 3 April 2019 Accepted: 24 April 2019 DOI: 10.1002/jimd.12104 REVIEW ARTICLE Recent advances in understanding the molecular genetic basis of mitochondrial disease Kyle Thompson1 | Jack J. Collier1 | Ruth I. C. Glasgow1 | Fiona M. Robertson1 | Angela Pyle2 | Emma L. Blakely1,3 | Charlotte L. Alston1,3 | Monika Oláhová1 | Robert McFarland1 | Robert W. Taylor1,3 1Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Abstract Newcastle University, Newcastle upon Mitochondrial disease is hugely diverse with respect to associated clinical presenta- Tyne, UK tions and underlying genetic causes, with pathogenic variants in over 300 disease 2 Wellcome Centre for Mitochondrial genes currently described. Approximately half of these have been discovered in the Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon last decade due to the increasingly widespread application of next generation Tyne, UK sequencing technologies, in particular unbiased, whole exome—and latterly, whole 3 NHS Highly Specialised Mitochondrial genome sequencing. These technologies allow more genetic data to be collected from Diagnostic Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, patients with mitochondrial disorders, continually improving the diagnostic success Newcastle upon Tyne, UK rate in a clinical setting. Despite these significant advances, some patients still remain without a definitive genetic diagnosis. Large datasets containing many variants of Correspondence Robert W. Taylor, Wellcome Centre for unknown significance have become a major challenge with next generation sequenc- Mitochondrial Research, Institute of ing strategies and these require significant functional validation to confirm pathoge- Neuroscience, Newcastle University, nicity. This interface between diagnostics and research is critical in continuing to Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. expand the list of known pathogenic variants and concomitantly enhance our knowl- Email: [email protected] edge of mitochondrial biology. The increasing use of whole exome sequencing, whole genome sequencing and other “omics” techniques such as transcriptomics and Communicating Editor: Verena Peters proteomics will generate even more data and allow further interrogation and valida- Funding information tion of genetic causes, including those outside of coding regions. This will improve Medical Research Council, Grant/Award Number: G0800674; National Institute for diagnostic yields still further and emphasizes the integral role that functional assess- Health Research, Grant/Award Number: NIHR- ment of variant causality plays in this process—the overarching focus of this review. HCS-D12-03-04; The Lily Foundation; UK NHS Highly Specialised Service for Rare KEYWORDS Mitochondrial Disorders; Wellcome Trust, diagnosis, mitochondrial disease, molecular mechanisms, next generation sequencing Grant/Award Number: 203105/Z/16/Z 1 | INTRODUCTION 1.1 | Mitochondrial disease overview Mitochondrial disorders are the most common group of inborn errors of metabolism with an estimated minimum Kyle Thompson and Jack J. Collier contributed equally to this study. disease prevalence in adults of 12.5 per 100 000,1 and This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM 36 wileyonlinelibrary.com/journal/jimd J Inherit Metab Dis. 2020;43:36–50. THOMPSON ET AL. 37 4.7 per 100 000 in children.2 “Mitochondrial disease” is a to, iron sulfur cluster formation,8 the citric acid cycle,9 regu- collective term for many different clinical disorders united lation of apoptosis10 and calcium homeostasis in conjunction by the common features of failure of mitochondrial function with the endoplasmic reticulum.11 and aberrant energy metabolism.3 Mitochondrial disorders Human mtDNA is a closed-circular molecule of can present at any age and result from pathogenic variants in 16 569 bp and encodes 37 genes; 13 polypeptides, 22 trans- either the nuclear genome (nDNA) or mitochondrial genome fer RNAs (tRNAs) and 2 ribosomal RNAs (rRNAs).12 The (mtDNA). Due to this dual genetic control of mitochondrial mitochondrial genome is exclusively maternally-inherited function, these disorders can be inherited with any inheri- and is present in multiple copies within cells. Cells can be tance pattern: sporadic, maternal, autosomal dominant, auto- homoplasmic, where all mtDNA molecules are identical, or somal recessive or X-linked. heteroplasmic, where two (or more) variant populations of Mitochondria are present in all nucleated cell types and mtDNA exist within one cell. Heteroplasmy levels are a fac- therefore, mitochondrial disease may affect any organ or tis- tor in determining the aforementioned clinical heterogeneity sue in the body. Some patients have an organ specific in patients harboring the common pathogenic m.3243A > G 13 disease—“pure” myopathy, cardiomyopathy or optic neu- variant. However, heteroplasmy does not fully explain the 14 ropathy, while others have multisystem involvement at pre- phenotypic variability with sex and heritable nuclear fac- sentation or acquire this during the course of their tors15 likely to play a role. progressive disease. While there may be some diagnostic, All 13 mtDNA-encoded proteins are essential hydropho- and potentially prognostic, utility in categorising the myriad bic components of the OXPHOS system located in the inner clinical features as particular syndromes e.g. MELAS (Mito- mitochondrial membrane (IMM). The OXPHOS system chondrial encephalomyopathy, lactic acidosis, and stroke- comprises five multi-subunit complexes and two electron like episodes); MERRF (Myoclonic epilepsy with ragged carriers (ubiquinone and cytochrome c). Complexes I-IV red fibres); LHON (Leber hereditary optic neuropathy); and the electron carriers constitute the electron transport NARP (Neuropathy, ataxia, and retinitis pigmentosa); Leigh chain, which establishes an electrochemical gradient across Syndrome and Pearson Syndrome, the reality is that many the IMM that is then dissipated via complex V (the F1FO patients do not fit easily into this syndromic classification. ATP synthase) to synthesize ATP. Individual OXPHOS A further complication is that genotype-phenotype correla- complexes can also combine into larger complexes; the crys- tions in mitochondrial disease are often poor, even within tal structures of some of these supercomplexes, including the these defined syndromes. For example, Leigh syndrome, mammalian respirasome, have recently been elucidated.16,17 which presents as a progressive neurodegenerative disorder In addition to the 13 polypeptides encoded by mtDNA, in childhood, exhibits marked genetic variability and is asso- more than 60 further nuclear-encoded respiratory chain pro- ciated with pathogenic variants in more than 75 different teins are translated in the cytosol and imported into mito- mtDNA or nDNA genes.4,5 Conversely, a single genotype chondria prior to incorporation into the OXPHOS can present with a range of phenotypes; the most common complexes. Indeed, the nuclear genome accounts for 99% of heteroplasmic pathogenic mtDNA variant, m.3243A > G, the mitochondrial proteome which is estimated to comprise can present with a classic MELAS phenotype, but also with 1158 total mitochondrial proteins.18 A large proportion of MIDD (Maternally-inherited diabetes and deafness), sensori- these proteins have important roles in OXPHOS, either neural hearing loss, myopathy, cardiomyopathy, seizures, directly as respiratory complex subunits, cofactors, assembly migraine, ataxia, cognitive impairment, bowel dysmotility, factors and substrate-generating upstream pathways, or more short stature, diabetes, external ophthalmoplegia or Leigh indirectly, for example, factors involved in the expression of syndrome and 9% of individuals are asymptomatic.6 The mtDNA-encoded genes. Mitochondrial gene expression vast clinical and genetic heterogeneity of mitochondrial dis- requires proteins involved in mtDNA maintenance, tran- ease coupled with poor genotype-phenotype correlations scription, RNA processing/maturation, translation and post- makes the genetic diagnosis of patients a challenging task. translational insertion into the IMM. Furthermore, all of these proteins need to be correctly targeted and imported into the mitochondria. Thus, any defects in mitochondrial 1.2 | Mitochondrial function and genetics protein import or the structure of the mitochondria, caused Mitochondria are dynamic organelles that are responsible for by aberrant cristae formation or abnormal membrane lipid the generation of adenosine triphosphate (ATP) via oxidative composition, as well as factors affecting mitochondrial fis- phosphorylation (OXPHOS); approximately 90% of the sion and fusion can also negatively impact the OXPHOS energy requirement of the cell is met through hydrolysis of system. The genetic heterogeneity of mitochondrial disor- ATP produced this way.7 However, mitochondria are also ders is a consequence of this wide range of proteins that involved in many other processes including, but not limited impact OXPHOS function. Over 300 mitochondrial disease- 38 THOMPSON ET AL. mtDNA pathogenic variants: 36/37 genes OXPHOS (CI) MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L,