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Incidential findings in exome sequencing

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As the incidence of clinical whole exome testing increases, it has become very important to discuss the possibility of unrelated, incidential findings with patients and their families. Dorscher et al(AJHG, 2013 (93) 631-640) just published the rate of incidential, actionable findings in 114 genes (which includes the ACMG recommended panel of 56 actionable genes) in 1000 […]



Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development.

Posted by & filed under Part 17: VITAMINS, _.

In a complex but interesting study, Padmanabhan et al. created transgenic mice with impaired folate metabolism because of heterozygosity for a knock-down allele for Mtrr (encoding methionine synthase reductase, which is necessary in mammals for the activation of methionine synthase). They then interbred these mice with wild-type controls through several generations and evaluated their wild-type […]



shared genetic etiology for different psychiatric disorders

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To examine shared genetic etiology among different psychiatric disorders Lee et al. used genome-wide genotype data (from the Psychiatric Genomics Consortium) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). After univariate and bivariate analysis, the genetic variation within and covariation between disorders was estimated. […]



FBXL4: A new gene implicated in mtDNA depletion

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Bonnen et al.,  in AJHG 2013 (93), 471-481 reported a new gene associated with an autosomal recessive disorder of mtDNA depeletion. This gene, FBLX4 was found through whole exome sequencing in a consanguinious family with multiple affected individuals.  Gai et al., also published an association of this gene with mitochondrial disease in the same edition of […]



Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION, Part 28: NEUROGENETICS, _.

Multiple-system atrophy (MSA) is an adult-onset neurodegenerative disease encompassing various combinations of parkinsonism, autonomic dysfunction, cerebellar ataxia and pyramidal dysfunction. As the neuropathologic diagnosis of MSA requires the finding of cytoplasmic aggregates of alpha-synuclein in oligodendroglia, it is classed among the alpha-synucleinopathies, alongside Parkinson disease and Lewy-body dementia. The disease is generally considered sporadic, though […]



PKU-BH4 responders and executive function/ white matter changes

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Blood blood phenylalanine (Phe), microstructural white matter integrity (evaluated by mean diffusivity from diffusion tensor imaging), and executive abilities were assessed in 12 PKU patients, known BH4 responders. Assessments were performed before initiation of treatment with BH4 (baseline) and repeated six months later (follow-up). Compared with baseline, Phe decreased by 51% during over four weeks […]



Energy Deficiency and GSD III

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Muscle weakness in Glycogen Storage Disease type III (debranching disease) is thought to be due to overall muscle wasting. However, Preisler N., et al (Mol Genet Metab. 2013 May;109(1):14-20) recently demonstrated that insufficient muscle glycogenolytic capacity, in combination with liver involvement, contributes significantly to muscle fatigue. This is an interesting finding, in light of the fact that rhabdomyolysis […]



Dimethylarginine and eNOS mitochondrial redistribution

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Asymmetric dimethylarginine is an inhibitor of endothelial nitric-oxide synthase by competing with l-arginine. In 2008, Sud et al showed that that asymmetric dimethylarginine  induces translocation of endothelial nitric-oxide synthase to mitochondria via a  protein nitration dependent mechanism, resulting in potential mitochondrial dysfunction (Sud N, Am. J. Physiol. Cell Physiol. 294, C1407–1418). In a more recent article (Rafikov et al. J […]



Genetic analysis in great apes

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Vuch et al (Genet Mol Res. 2013 May 21;12(2):1731-9) published a study in which they attempted to infer a specific genetic abnormality (Beta thalassemia) based on dysmorphic skeletons of two ape skeletons of closely related but different species. They extracted tooth DNA from each of the skeletons and sequenced the beta globin locus. The beta […]



ATP synthase

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Complex V of the respiratory chain, or ATP synthase, uses the energy created by the proton electrochemical gradient across the inner mitochondrial membrane to phosphorylate ADP to ATP. It consists of 2 functional domains F1 and Fo connected by a stalk domain. Complex V abnormalities make up the smallest percentage of known disorders of mitochondrial respiratory […]