Editorial Board
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Front Cover
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Genome-wide association study of serum coenzyme Q10 levels identifies susceptibility loci linked to neuronal diseases
Coenzyme Q10 (CoQ10) is a lipophilic redox molecule that is present in membranes of almost all cells in human tissues. CoQ10 is, amongst other functions, essential for the respiratory transport chain and is a modulator of inflammatory processes and gene expression. Rare monogenetic CoQ10 deficiencies show noticeable symptoms in tissues (e.g. kidney) and cell types (e.g. neurons) with a high energy demand. To identify common genetic variants influencing serum CoQ10 levels, we performed a fixed effects meta-analysis in two independent cross-sectional Northern German cohorts comprising 1300 individuals in total. We identified...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Degenhardt, F., Niklowitz, P., Szymczak, S., Jacobs, G., Lieb, W., Menke, T., Laudes, M., Esko, T., Weidinger, S., Franke, A., Döring, F., Onur, S. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Identification of a novel susceptibility locus at 16q23.1 associated with childhood acute lymphoblastic leukemia in Han Chinese
Recently, genome-wide association studies (GWAS) have identified several susceptibility loci for childhood acute lymphoblastic leukemia (ALL) in populations of European descent; only a few loci could be confirmed in Asian populations because of those populations’ genetic heterogeneity. To identify genetic factors associated with childhood ALL risk in the Chinese population, we performed a three-stage GWAS of 1184 childhood ALL cases and 3219 non-ALL controls. The combined analysis identified a new locus (rs1121404 in WWOX) at 16q23.1 associated with childhood ALL susceptibility (odds ratio (OR) = 1.38, P = 5.29 x 10&...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Shi, Y., Du, M., Fang, Y., Tong, N., Zhai, X., Sheng, X., Li, Z., Xue, Y., Li, J., Chu, H., Chen, J., Song, Z., Shen, J., Ji, J., Li, X., Hu, Z., Shen, H., Xu, J., Wang, M., Zhang, Z. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy
This study provides evidence for a defined, intrinsic contribution of glial cells to SMA disease pathogenesis and suggests that therapies designed to include Schwann cells in their target tissues are likely to be required in order to rescue myelination defects and associated disease symptoms. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Hunter, G., Powis, R. A., Jones, R. A., Groen, E. J. N., Shorrock, H. K., Lane, F. M., Zheng, Y., Sherman, D. L., Brophy, P. J., Gillingwater, T. H. Tags: ARTICLES Source Type: research
Characterization of SKAP/kinastrin isoforms: the N-terminus defines tissue specificity and Pontin binding
Small Kinetochore-Associated Protein (SKAP)/Kinastrin is a multifunctional protein with proposed roles in mitosis, apoptosis and cell migration. Exact mechanisms underlying its activities in these cellular processes are not completely understood. SKAP is predicted to have different isoforms, however, previous studies did not differentiate between them. Since distinct molecular architectures of protein isoforms often influence their localization and functions, this study aimed to examine the expression profile and functional differences between SKAP isoforms in human and mouse. Analyses of various human tissues and cells of...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Cindric Vranesic, A., Reiche, J., Hoischen, C., Wohlmann, A., Bratsch, J., Friedrich, K., Günes, B., Cappallo-Obermann, H., Kirchhoff, C., Diekmann, S., Günes, C., Huber, O. Tags: ARTICLES Source Type: research
ER-shaping proteins are required for ER and mitochondrial network organization in motor neurons
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by degeneration of the longest motor neurons in the corticospinal tract, leading to muscle weakness and spasticity of the lower limbs. Pathogenic variants in genes encoding proteins that shape the endoplasmic-reticulum (ER) network are a leading cause of HSP, however, the mechanisms by which loss of ER-shaping proteins underpin degeneration of selective neurons in HSP remain poorly understood. To begin to address this, we have generated a novel in vivo model of HSP in Drosophila melanogaster by targeted knockdown of the ER-shapin...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Fowler, P. C., OSullivan, N. C. Tags: ARTICLES Source Type: research
Oxygen consumption deficit in Huntington disease mouse brain under metabolic stress
In vivo evidence for brain mitochondrial dysfunction in animal models of Huntington disease (HD) is scarce. We applied the novel 17O magnetic resonance spectroscopy (MRS) technique on R6/2 mice to directly determine rates of oxygen consumption (CMRO2) and assess mitochondrial function in vivo. Basal respiration and maximal CMRO2 in the presence of the mitochondrial uncoupler dinitrophenol (DNP) were compared using 16.4 T in isoflurane anesthetized wild type (WT) and HD mice at 9 weeks. At rest, striatal CMRO2 of R6/2 mice was equivalent to that of WT, indicating comparable mitochondrial output despite onset of motor sympto...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Lou, S., Lepak, V. C., Eberly, L. E., Roth, B., Cui, W., Zhu, X.-H., Öz, G., Dubinsky, J. M. Tags: ARTICLES Source Type: research
Dominant and recessive mutations in rhodopsin activate different cell death pathways
Mutations in rhodopsin (RHO) are a common cause of retinal dystrophy and can be transmitted by dominant or recessive inheritance. Clinical symptoms caused by dominant and recessive mutations in patients and animal models are very similar but the molecular mechanisms leading to retinal degeneration may differ. We characterized three murine models of retina degeneration caused by either Rho loss of function or expression of the P23H dominant mutation in Rho. Rho loss of function is characterized by activation of calpains and apoptosis-inducing factor (Aif) in dying photoreceptors. Retinas bearing the P23H dominant mutations ...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Comitato, A., Di Salvo, M. T., Turchiano, G., Montanari, M., Sakami, S., Palczewski, K., Marigo, V. Tags: ARTICLES Source Type: research
Filamin C is a highly dynamic protein associated with fast repair of myofibrillar microdamage
Filamin c (FLNc) is a large dimeric actin-binding protein located at premyofibrils, myofibrillar Z-discs and myofibrillar attachment sites of striated muscle cells, where it is involved in mechanical stabilization, mechanosensation and intracellular signaling. Mutations in the gene encoding FLNc give rise to skeletal muscle diseases and cardiomyopathies. Here, we demonstrate by fluorescence recovery after photobleaching that a large fraction of FLNc is highly mobile in cultured neonatal mouse cardiomyocytes and in cardiac and skeletal muscles of live transgenic zebrafish embryos. Analysis of cardiomyocytes from Xirp1 and X...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Leber, Y., Ruparelia, A. A., Kirfel, G., van der Ven, P. F. M., Hoffmann, B., Merkel, R., Bryson-Richardson, R. J., Fürst, D. O. Tags: ARTICLES Source Type: research
Oxidative metabolism and Ca2+ handling in isolated brain mitochondria and striatal neurons from R6/2 mice, a model of Huntingtons disease
Alterations in oxidative metabolism and defects in mitochondrial Ca2+ handling have been implicated in the pathology of Huntington’s disease (HD), but existing data are contradictory. We investigated the effect of human mHtt fragments on oxidative metabolism and Ca2+ handling in isolated brain mitochondria and cultured striatal neurons from the R6/2 mouse model of HD. Non-synaptic and synaptic mitochondria isolated from the brains of R6/2 mice had similar respiratory rates and Ca2+ uptake capacity compared with mitochondria from wild-type (WT) mice. Respiratory activity of cultured striatal neurons measured with Seah...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Hamilton, J., Pellman, J. J., Brustovetsky, T., Harris, R. A., Brustovetsky, N. Tags: ARTICLES Source Type: research
Suppression of the motor deficit in a mucolipidosis type IV mouse model by bone marrow transplantation
Mucolipidosis IV (MLIV) is a severe lysosomal storage disorder, which results from loss of the TRPML1 channel. MLIV causes multiple impairments in young children, including severe motor deficits. Currently, there is no effective treatment. Using a Drosophila MLIV model, we showed previously that introduction of trpml+ in phagocytic glia rescued the locomotor deficit by removing early dying neurons, thereby preventing amplification of neuronal death from cytotoxicity. Because microglia, which are phagocytic cells in the mammalian brain, are bone marrow derived, and cross the blood–brain barrier, we used a mouse MLIV m...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Walker, M. T., Montell, C. Tags: ARTICLES Source Type: research
Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects
Mutations in β-catenin (CTNNB1) have been implicated in cancer and mental disorders. Recently, loss-of-function mutations of CTNNB1 were linked to intellectual disability (ID), and rare mutations were identified in patients with autism spectrum disorder (ASD). As a key regulator of the canonical Wnt pathway, CTNNB1 plays an essential role in neurodevelopment. However, the function of CTNNB1 in specific neuronal subtypes is unclear. To understand how CTNNB1 deficiency contributes to ASD, we generated CTNNB1 conditional knockout (cKO) mice in parvalbumin interneurons. The cKO mice had increased anxiety, but had no overa...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Dong, F., Jiang, J., McSweeney, C., Zou, D., Liu, L., Mao, Y. Tags: ARTICLES Source Type: research
Altered secondary structure of Dynorphin A associates with loss of opioid signalling and NMDA-mediated excitotoxicity in SCA23
Spinocerebellar ataxia type 23 (SCA23) is caused by missense mutations in prodynorphin, encoding the precursor protein for the opioid neuropeptides α-neoendorphin, Dynorphin (Dyn) A and Dyn B, leading to neurotoxic elevated mutant Dyn A levels. Dyn A acts on opioid receptors to reduce pain in the spinal cord, but its cerebellar function remains largely unknown. Increased concentration of or prolonged exposure to Dyn A is neurotoxic and these deleterious effects are very likely caused by an N-methyl-d-aspartate-mediated non-opioid mechanism as Dyn A peptides were shown to bind NMDA receptors and potentiate their gluta...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Smeets, C. J. L. M., Zmorzynska, J., Melo, M. N., Stargardt, A., Dooley, C., Bakalkin, G., McLaughlin, J., Sinke, R. J., Marrink, S.-J., Reits, E., Verbeek, D. S. Tags: ARTICLES Source Type: research
The contribution of mutant GBA to the development of Parkinson disease in Drosophila
In this study, we used the fruit fly Drosophila melanogaster to show that development of PD in carriers of GD mutations results from the presence of mutant GBA alleles. Drosophila has two GBA orthologs (CG31148 and CG31414), each of which has a minos insertion, which creates C-terminal deletion in the encoded GCase. Flies double heterozygous for the endogenous mutant GBA orthologs presented Unfolded Protein Response (UPR) and developed parkinsonian signs, manifested by death of dopaminergic cells, defective locomotion and a shorter life span. We also established transgenic flies carrying the mutant human N370S, L444P and t...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Maor, G., Cabasso, O., Krivoruk, O., Rodriguez, J., Steller, H., Segal, D., Horowitz, M. Tags: ARTICLES Source Type: research
