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      Phenotypic heterogeneity in m.3243A>G mitochondrial disease: The role of nuclear factors

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          Abstract

          Objective

          The pathogenic mitochondrial DNA m.3243A>G mutation is associated with a wide range of clinical features, making disease prognosis extremely difficult to predict. We aimed to understand the cause of this heterogeneity.

          Methods

          We examined the phenotypic profile of 238 adult m.3243A>G carriers (patients and asymptomatic carriers) from the UK MRC Mitochondrial Disease Patient Cohort using the Newcastle Mitochondrial Disease Adult Scale. We modeled the role of risk factors for the development of specific phenotypes using proportional odds logistic regression. As mitochondria are under the dual control of their own and the nuclear genome, we examined the role of additive nuclear genetic factors in the development of these phenotypes within 46 pedigrees from the cohort.

          Results

          Seizures and stroke‐like episodes affect 25% and 17% of patients, respectively; more common features include hearing impairment, gastrointestinal disturbance, psychiatric involvement, and ataxia. Age, age‐adjusted blood heteroplasmy levels, and sex are poor predictors of phenotypic severity. Hearing impairment, diabetes, and encephalopathy show the strongest associations, but pseudo‐ R 2 values are low (0.14–0.17). We found a high heritability estimate for psychiatric involvement ( h 2=0.76, P = 0.0003) and moderate estimates for cognition ( h 2=0.46, P = 0.0021), ataxia ( h 2 = 0.45, P = 0.0011), migraine ( h 2 = 0.41, P = 0.0138), and hearing impairment (h 2 = 0.40, P = 0.0050).

          Interpretation

          Our results provide good evidence for the presence of nuclear genetic factors influencing clinical outcomes in m.3234A>G‐related disease, paving the way for future work identifying these through large‐scale genetic linkage and association studies, increasing our understanding of the pathogenicity of m.3243A>G and providing improved estimates of prognosis.

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          Most cited references28

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          Genetic epidemiology of major depression: review and meta-analysis.

          The authors conducted a meta-analysis of relevant data from primary studies of the genetic epidemiology of major depression. The authors searched MEDLINE and the reference lists of previous review articles to identify relevant primary studies. On the basis of a review of family, adoption, and twin studies that met specific inclusion criteria, the authors derived quantitative summary statistics. Five family studies met the inclusion criteria. The odds ratios for proband (subjects with major depression or comparison subjects) versus first-degree relative status (affected or unaffected with major depression) were homogeneous across the five studies (Mantel-Haenszel odds ratio=2.84, 95% CI=2.31-3.49). No adoption study met the inclusion criteria, but the results of two of the three reports were consistent with genetic influences on liability to major depression. Five twin studies met the inclusion criteria, and their statistical summation suggested that familial aggregation was due to additive genetic effects (point estimate of heritability of liability=37%, 95% CI=31%-42%), with a minimal contribution of environmental effects common to siblings (point estimate=0%, 95% CI=0%-5%), and substantial individual-specific environmental effects/measurement error (point estimate=63%, 95% CI=58%-67%). The literature suggests that recurrence best predicts the familial aggregation of major depression. Major depression is a familial disorder, and its familiality mostly or entirely results from genetic influences. Environmental influences specific to an individual are also etiologically significant. Major depression is a complex disorder that does not result from either genetic or environmental influences alone but rather from both. These findings are notably consistent across samples and methods and are likely to be generally applicable.
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            The measurement of urban travel demand

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              Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness.

              Non-insulin-dependent (type II) diabetes mellitus (NIDDM) is characterized by hyperglycaemia and insulin resistance, and affects nearly 5% of the general population. Inherited factors are important for its development, but the genes involved are unknown. We have identified a large pedigree in which NIDDM, in combination with a sensorineural hearing loss, is maternally inherited. The maternal inheritance and the observed decrease in mitochondrial enzyme activities of the respiratory chain indicate a genetic defect in the mitochondrial DNA. An A to G transition was identified at nucleotide 3,243, a conserved position in the mitochondrial gene for tRNA(Leu)(UUR). This mutation cosegregates with the disease in this family and is absent in controls, and indicates that a point mutation in mitochondrial DNA is a pathogenetic factor for NIDDM.
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                Author and article information

                Contributors
                sarah.pickett@ncl.ac.uk
                Journal
                Ann Clin Transl Neurol
                Ann Clin Transl Neurol
                10.1002/(ISSN)2328-9503
                ACN3
                Annals of Clinical and Translational Neurology
                John Wiley and Sons Inc. (Hoboken )
                2328-9503
                07 February 2018
                March 2018
                : 5
                : 3 ( doiID: 10.1002/acn3.2018.5.issue-3 )
                : 333-345
                Affiliations
                [ 1 ] Wellcome Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle upon Tyne UK
                [ 2 ] Institute of Genetic Medicine Newcastle University Newcastle upon Tyne UK
                [ 3 ]Present address: Kinghorn Centre for Clinical Genomics Garvan Institute Sydney NSW Australia
                Author notes
                [*] [* ] Correspondence

                Sarah J Pickett, Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Framlington Place, NE2 4HH, Newcastle upon Tyne, UK. Tel: +44 191 2085397; Fax: +44 191 2824373; E‐mail: sarah.pickett@ 123456ncl.ac.uk

                Article
                ACN3532
                10.1002/acn3.532
                5846390
                671fbb70-9ee7-4118-995b-3486be3821ee
                © 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

                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.

                Page count
                Figures: 3, Tables: 3, Pages: 13, Words: 7925
                Product
                Funding
                Funded by: Wellcome Trust
                Award ID: 102858/Z/13/Z
                Award ID: 204709/Z/16/Z
                Funded by: Wellcome Centre for Mitochondrial Research
                Award ID: 203105/Z/16/Z
                Funded by: Medical Research Council (MRC) Centre for TranslationalResearch in Neuromuscular Disease,
                Award ID: G0800674
                Funded by: Lily Foundation
                Funded by: UK NIHR Biomedical Research Centre for Ageing
                Funded by: Age‐related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust
                Funded by: UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children
                This work was funded by Wellcome Trust grants 102858/Z/13/Z and 204709/Z/16/Z; Wellcome Centre for Mitochondrial Research grant 203105/Z/16/Z; Medical Research Council (MRC) Centre for TranslationalResearch in Neuromuscular Disease, grant G0800674; Lily Foundation grant ; UK NIHR Biomedical Research Centre for Ageing grant ; Age‐related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust grant ; UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children grant .
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                acn3532
                March 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:12.03.2018

                mitochondrial disease,m.3243a>g,heritability
                mitochondrial disease, m.3243a>g, heritability

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