Mitochondrial respiratory chain disorders in the Old Order Amish population

Ghaloul‐Gonzalez, Lina; Goldstein, Amy; Vockley, Catherine Walsh; Dobrowolski, Steven F.; Biery, Amy; Irani, Afifa; Ibarra, Jordan; Morton, D. Holmes; Mohsen, Al‐Walid; Vockley, Jerry

doi:10.1016/j.ymgme.2016.06.005

Cited by 6 publications

(14 citation statements)

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“…Detailed neuroimaging studies have been reported for three out of six patients with Leigh syndrome. Bilateral symmetrical lesions of the midbrain and/or basal ganglia, characteristic of Leigh Syndrome, were reported for these three patients ( Ghaloul-Gonzalez et al, 2016 ; Herzer et al, 2010 ; Hoefs et al, 2009 ). Additionally, two patients exhibited SN involvement, out of which one patient exhibited depigmentation of the SN, typical of DA neuronal loss ( Ghaloul-Gonzalez et al, 2016 ; Herzer et al, 2010 ).…”

Section: The Strange Case Of Ndufaf2mentioning

confidence: 77%

“…Decreased CI activity in the skeletal muscle or fibroblasts was confirmed in seven patients ( Herzer et al, 2010 ; Janssen et al, 2009 ; Koene et al, 2012 ), which is expected as NDUFAF2 has been implicated in both CI assembly ( Adjobo-Hermans et al, 2020 ; Guerrero-Castillo et al, 2017 ; Ogilvie et al, 2005 ; Vogel et al, 2007 ) and activity ( Schlehe et al, 2013 ). In 11 out of the 12 cases, the loss of NDUFAF2 was due to homozygous or hemizygous mutations that lead to the termination of NDUFAF2 synthesis [resulting in the variations: M1L, W3X, Y38X, W74X, I35SfsX17, A73GfsX5, R45X], or homozygous deletions in the NDUFAF2 gene / 450 kb deletion of a region including the NDUFAF2 gene ( Barghuti et al, 2008 ; Calvo et al, 2010 ; Fassone and Rahman, 2012 ; Ghaloul-Gonzalez et al, 2016 ; Herzer et al, 2010 ; Hoefs et al, 2009 ; Janssen et al, 2009 ; Koene et al, 2012 ; Ogilvie et al, 2005 ).…”

Section: The Strange Case Of Ndufaf2mentioning

confidence: 99%

“…Amongst the 11 patients that were studied closely, all exhibited early-onset encephalopathies with a lifespan ranging from nine to 24 months for ten patients and 13 years for one patient ( Barghuti et al, 2008 ; Calvo et al, 2010 ; Fassone and Rahman, 2012 ; Ghaloul-Gonzalez et al, 2016 ; Herzer et al, 2010 ; Hoefs et al, 2009 ; Janssen et al, 2009 ; Koene et al, 2012 ; Ogilvie et al, 2005 ). Six patients were characterized with the neuropathology of Leigh syndrome, a disorder that also commonly includes SN involvement ( Calvo et al, 2010 ; Ghaloul-Gonzalez et al, 2016 ; Herzer et al, 2010 ; Hoefs et al, 2009 ). Detailed neuroimaging studies have been reported for three out of six patients with Leigh syndrome.…”

Section: The Strange Case Of Ndufaf2mentioning

confidence: 99%

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Is there a special relationship between complex I activity and nigral neuronal loss in Parkinson’s disease? A critical reappraisal

Subrahmanian

LaVoie

2021

Brain Research

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Section: The Strange Case Of Ndufaf2mentioning

confidence: 77%

Section: The Strange Case Of Ndufaf2mentioning

confidence: 99%

Section: The Strange Case Of Ndufaf2mentioning

confidence: 99%

See 1 more Smart Citation

Is there a special relationship between complex I activity and nigral neuronal loss in Parkinson’s disease? A critical reappraisal

Subrahmanian

LaVoie

2021

Brain Research

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“…Two of the strongest genes with differential expression in the concordant subset were NAGA (an enzyme cleaving specific moieties from glycoconjugates) and NDUFAF2 (part of the mitochondrial complex [MIM: 609653]); rare mutations in each of these genes are associated with early and severe neurodevelopmental disorders. 79,80 TWAS of the discordant subset revealed synaptic genes including C4A, which plays a key role in synaptic pruning, 78 as well as other genes essential to synapse structure and function; such genes include ARL3 (MIM: 604695), FXR1 (MIM: 600819), and CNNM2 (MIM: 607803). Moreover, pathway analysis of S-Predixcan results (Table 3) demonstrated that the strongest gene set associated with the concordant subset was cell-to-cell adhesion via plasma-membrane adhesion molecules (GO: 0098742); this gene set encompasses processes such as those necessary for neural tube closure, cerebral cortex migration, and neuronal-glial interactions.…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways

Lam

Hill

Trampush

et al. 2019

The American Journal of Human Genetics

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Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected (''concordant'') direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive (''discordant'') relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 3 10 À8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

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“…Additionally, transcriptome-wide analysis using S-Predixcan pointed towards the same distinction between Concordant and Discordant genes and pathways. Two of the strongest genes with differential expression in the Concordant subset were NAGA (an enzyme cleaving specific moieties from glycoconjugates) and NDUFAF2 (part of the mitochondrial complex); rare mutations in each of these genes are associated with early and severe neurodevelopmental disorders 97,98 . TWAS of the discordant subset revealed synaptic genes including C4A, which plays a key role in synaptic pruning 96 , as well as other transcripts essential to synapse structure and function such as ARL3, FXR1, and CNNM2.…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways

Lam

Hill

Trampush

et al. 2019

Preprint

View full text Add to dashboard Cite

Liability to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published GWAS in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results.Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("Concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants demonstrating the counterintuitive ("Discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education and/or schizophrenia at p<5x10 −8 . Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs, and many of these have been validated by larger, more recent single-phenotype GWAS.Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms: early neurodevelopmental pathways that characterize concordant allelic variation, and adulthood synaptic pruning pathways that were linked to the paradoxical positive genetic association between education and schizophrenia. Further, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia, but also to the broader biological dimensions that are implicated in both general health outcomes and psychiatric illness.

show abstract

Mitochondrial respiratory chain disorders in the Old Order Amish population

Cited by 6 publications

References 30 publications

Is there a special relationship between complex I activity and nigral neuronal loss in Parkinson’s disease? A critical reappraisal

Is there a special relationship between complex I activity and nigral neuronal loss in Parkinson’s disease? A critical reappraisal

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways

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