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Human Molecular Genetics

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https://www.readbyqxmd.com/read/28444311/expression-of-als-ftd-linked-mutant-ccnf-in-zebrafish-leads-to-increased-cell-death-in-the-spinal-cord-and-an-aberrant-motor-phenotype
#1
Alison L Hogan, Emily K Don, Stephanie L Rayner, Albert Lee, Angela S Laird, Maxinne Watchon, Claire Winnick, Ingrid S Tarr, Marco Morsch, Jennifer A Fifita, Serene Gwee, Isabel Formella, Elinor Hortle, Kristy Yuan, Mark P Molloy, Kelly L Williams, Garth A Nicholson, Roger S Chung, Ian P Blair, Nicholas J Cole
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease characterised by the death of upper and lower motor neurons. Approximately 10% of cases have a known family history of ALS and disease-linked mutations in multiple genes have been identified. ALS-linked mutations in CCNF were recently reported, however the pathogenic mechanisms associated with these mutations are yet to be established. To investigate possible disease mechanisms, we developed in vitro and in vivo models based on an ALS-linked missense mutation in CCNF...
April 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28444310/arl3-and-rp2-regulate-the-trafficking-of-ciliary-tip-kinesins
#2
Nele Schwarz, Amelia Lane, Katarina Jovanovich, David A Parfitt, Monica Aguila, Clare L Thompson, Lyndon da Cruz, Peter J Coffey, J Paul Chapple, Alison J Hardcastle, Michael E Cheetham
Ciliary trafficking defects are the underlying cause of many ciliopathies, including Retinitis Pigmentosa (RP). Anterograde intraflagellar transport (IFT) is mediated by kinesin motor proteins; however, the function of the homodimeric Kif17 motor in cilia is poorly understood, whereas Kif7 is known to play an important role in stabilising cilia tips. Here we identified the ciliary tip kinesins Kif7 and Kif17 as novel interaction partners of the small GTPase Arl3 and its regulatory GTPase activating protein (GAP) Retinitis Pigmentosa 2 (RP2)...
April 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28444304/a-frequent-oligogenic-involvement-in-congenital-hypothyroidism
#3
Tiziana de Filippis, Giulia Gelmini, Elvezia Paraboschi, Maria Cristina Vigone, Marianna Di Frenna, Federica Marelli, Marco Bonomi, Alessandra Cassio, Daniela Larizza, Mirella Moro, Giorgio Radetti, Mariacarolina Salerno, Diego Ardissino, Giovanna Weber, Davide Gentilini, Fabiana Guizzardi, Stefano Duga, Luca Persani
Congenital Hypothyroidism (CH), the most frequent form of preventable mental retardation, is predicted to have a relevant genetic origin. However, CH is frequently reported to be sporadic and candidate gene variations were found in < 10% of the investigated patients. Here, we characterize the involvement of 11 candidate genes through a systematic Next Generation Sequencing (NGS) analysis. The NGS was performed in 177 unrelated CH patients (94 gland-in-situ; 83 dysgenesis) and in 3,538 control subjects...
April 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28444230/apoe-%C3%AE%C2%B54-%C3%AE%C2%B54-diminishes-neurotrophic-function-of-human-ipsc-derived-astrocytes
#4
Jing Zhao, Mary D Davis, Yuka Atagi, Mitsuru Shinohara, Neill R Graff-Radford, Steven G Younkin, Zbigniew K Wszolek, Takahisa Kanekiyo, Guojun Bu
The ε4 allele of the APOE gene encoding apolipoprotein E (apoE) is a strong genetic risk factor for aging-related cognitive decline as well as late-onset Alzheimer's disease (AD) compared to the common ε3 allele. In the central nervous system, apoE is produced primarily by astrocytes and functions in transporting lipids including cholesterol to support neuronal homeostasis and synaptic integrity. Although mouse models and corresponding primary cells have provided valuable tools for studying apoE isoform-dependent functions, recent studies have shown that human astrocytes have distinct gene expression profile compare with rodent astrocytes...
April 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28444193/quantitative-assessment-of-timing-efficiency-specificity-and-genetic-mosaicism-of-crispr-cas9-mediated-gene-editing-of-hemoglobin-beta-gene-in-rhesus-monkey-embryos
#5
Uros Midic, Pei-Hsuan Hung, Kailey A Vincent, Benjamin Goheen, Patrick G Schupp, Diane D Chen, Daniel E Bauer, Catherine A VandeVoort, Keith E Latham
Gene editing technologies offer new options for developing novel biomedical research models and for gene and stem cell based therapies. However, applications in many species demand high efficiencies, specificity, and a thorough understanding of likely editing outcomes. To date, overall efficiencies, rates of off-targeting, and degree of genetic mosaicism have not been well-characterized for most species, limiting our ability to optimize methods. As a model gene for measuring these parameters of CRISPR/Cas9 application in a primate species (rhesus monkey), we selected the β-hemoglobin gene (HBB), which also has high relevance to potential application of gene editing and stem-cell technologies for treating human disease...
April 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28444186/frataxin-deficiency-impairs-mitochondrial-biogenesis-in-cells-mice-and-humans
#6
Mittal J Jasoliya, Marissa Z McMackin, Chelsea K Henderson, Susan L Perlman, Gino A Cortopassi
Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by inherited deficiency of the mitochondrial protein Frataxin (FXN), which has no approved therapy and is an area in which biomarkers are needed for clinical development. Here we investigated the consequences of FXN deficiency in patient derived FRDA fibroblast cell models, the FRDA mouse model KIKO, and in whole blood collected from FRDA patients. We observed decreased mitochondrial copy number in all the three FRDA models tested: cells, mice and patient blood...
April 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28444183/calcium-dysregulation-and-cdk5-atm-pathway-involved-in-a-mouse-model-of-fragile-x-associated-tremor-ataxia-syndrome
#7
Gaëlle Robin, José R López, Glenda M Espinal, Susan Hulsizer, Paul J Hagerman, Isaac N Pessah
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurological disorder that affects premutation carriers with 55-200 CGG-expansion repeats (preCGG) in FMR1, presenting with early alterations in neuronal network formation and function that precede neurodegeneration. Whether intranuclear inclusions containing DNA damage response (DDR) proteins, are causally linked to abnormal synaptic function, neuronal growth and survival are unknown. In a mouse that harbors a premutation CGG expansion (preCGG), cortical and hippocampal FMRP expression is moderately reduced from birth through adulthood, with greater FMRP reductions in the soma than in the neurite, despite several-fold elevation of Fmr1 mRNA levels...
April 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28430982/evidence-of-nuclei-encoded-spliceosome-mediating-splicing-of-mitochondrial-rna
#8
Roberto H Herai, Priscilla D Negraes, Alysson R Muotri
Mitochondria are thought to have originated as free-living prokaryotes. Mitochondria organelles have small circular genomes with substantial structural (absence of histones and introns) and genetic similarity to bacteria. Contrary to the prevailing concept of intronless mitochondria, here we present evidences that mitochondrial RNA transcripts (mtRNA) are not limited to policystronic molecules, but also processed as nuclei-like transcripts that are differentially spliced and expressed in a cell-type specific manner...
April 19, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28431142/respiratory-chain-enzyme-deficiency-induces-mitochondrial-location-of-actin-binding-gelsolin-to-modulate-the-oligomerization-of-vdac-complexes-and-cell-survival
#9
Alberto García-Bartolomé, Ana Peñas, Lorena Marín-Buera, Teresa Lobo-Jarne, Rafael Pérez-Pérez, María Morán, Joaquín Arenas, Miguel A Martín, Cristina Ugalde
Despite considerable knowledge on the genetic basis of mitochondrial disorders, their pathophysiological consequences remain poorly understood. We previously used 2D-DIGE analyses to define a protein profile characteristic for respiratory chain complex III-deficiency that included a significant overexpression of cytosolic Gelsolin (GSN), a cytoskeletal protein that regulates the severing and capping of the actin filaments. Biochemical and immunofluorescence assays confirmed a specific increase of GSN levels in the mitochondria from patientś fibroblasts and from transmitochondrial cybrids with complex III assembly defects...
April 18, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28430993/a-multi-systemic-mitochondrial-disorder-due-to-a-dominant-p-y955h-disease-variant-in-dna-polymerase-gamma
#10
Triinu Siibak, Paula Clemente, Ana Bratic, Helene Bruhn, Timo E S Kauppila, Bertil Macao, Florian A Schober, Nicole Lesko, Rolf Wibom, Karin Naess, Inger Nennesmo, Anna Wedell, Bradley Peter, Christoph Freyer, Maria Falkenberg, Anna Wredenberg
Mutations in the mitochondrial DNA polymerase, POLG, are associated with a variety of clinical presentations, ranging from early onset fatal brain disease in Alpers syndrome to chronic progressive external ophthalmoplegia. The majority of mutations are linked with disturbances of mitochondrial DNA (mtDNA) integrity and maintenance. On a molecular level, depending on their location within the enzyme, mutations either lead to mtDNA depletion or the accumulation of multiple mtDNA deletions, and in some cases these molecular changes can be correlated to the clinical presentation...
April 17, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28419360/p4ha1-mutations-cause-a-unique-congenital-disorder-of-connective-tissue-involving-tendon-bone-muscle-and-the-eye
#11
Yaqun Zou, Sandra Donkervoort, Antti M Salo, A Reghan Foley, Aileen M Barnes, Ying Hu, Elena Makareeva, Meganne E Leach, Payam Mohassel, Jahannaz Dastgir, Matthew A Deardorff, Ronald D Cohn, Wendy O DiNonno, Fransiska Malfait, Monkol Lek, Sergey Leikin, Joan C Marini, Johanna Myllyharju, Carsten G Bönnemann
Collagen prolyl 4-hydroxylases (C-P4Hs) play a central role in the formation and stabilization of the triple helical domain of collagens. P4HA1 encodes the catalytic α(I) subunit of the main C-P4H isoenzyme (C-P4H-I). We now report human bi-allelic P4HA1 mutations in a family with a congenital-onset disorder of connective tissue, manifesting as early-onset joint hypermobility, joint contractures, muscle weakness and bone dysplasia as well as high myopia, with evidence of clinical improvement of motor function over time in the surviving patient...
April 13, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28402427/bdnf-overexpression-prevents-cognitive-deficit-elicited-by-adolescent-cannabis-exposure-and-host-susceptibility-interaction
#12
Hadar Segal-Gavish, Neta Gazit, Yael Barhum, Tali Ben-Zur, Michal Taler, Shay Henry Hornfeld, Irit Gil-Ad, Abraham Weizman, Inna Slutsky, Minae Niwa, Atsushi Kamiya, Akira Sawa, Daniel Offen, Ran Barzilay
Cannabis abuse in adolescence is associated with increased risk of psychotic disorders. Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Disrupted-In-Schizophrenia-1 (DISC1) protein is a driver for major mental illness by influencing neurodevelopmental processes. Here, utilizing a unique mouse model based on host (DISC1) X environment (THC administration) interaction, we aimed at studying the pathobiological basis through which THC exposure elicits psychiatric manifestations...
April 11, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28398555/biophysical-and-functional-characterization-of-hippocalcin-mutants-responsible-for-human-dystonia
#13
Nordine Helassa, Svetlana V Antonyuk, Lu-Yun Lian, Lee P Haynes, Robert D Burgoyne
Dystonia is a neurological movement disorder that forces the body into twisting, repetitive movements or sometimes painful abnormal postures. With the advent of next-generation sequencing technologies, the homozygous mutations T71N and A190T in the neuronal calcium sensor (NCS) hippocalcin were identified as the genetic cause of primary isolated dystonia (DYT2 dystonia). However, the effect of these mutations on the physiological role of hippocalcin has not yet been elucidated. Using a multidisciplinary approach, we demonstrated that hippocalcin oligomerises in a calcium-dependent manner and binds to voltage-gated calcium channels...
April 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28398517/depolarization-causes-the-formation-of-a-ternary-complex-between-glialcam-mlc1-and-clc-2-in-astrocytes-implications-in-megalencephalic-leukoencephalopathy
#14
Sònia Sirisi, Xabier Elorza-Vidal, Tanit Arnedo, Mercedes Armand-Ugón, Gerard Callejo, Xavier Capdevila-Nortes, Tania López-Hernández, Uwe Schulte, Alejandro Barrallo-Gimeno, Virginia Nunes, Xavier Gasull, Raúl Estévez
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy caused by mutations in either MLC1 or GLIALCAM. GlialCAM is necessary for the correct targeting of MLC1, but also for the targeting of the Cl- channel ClC-2. Furthermore, GlialCAM modifies ClC-2 functional properties in vitro. However, in vivo studies in GlialCAM-/- mice have shown that the modification of ClC-2 activity only occurs in oligodendrocytes, despite GlialCAM and ClC-2 being expressed in astrocytes. Thus, the relationship between GlialCAM, MLC1 and ClC-2 in astrocytes is unknown...
April 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28398513/a-rare-splice-donor-mutation-in-the-haptoglobin-gene-associates-with-blood-lipid-levels-and-coronary-artery-disease
#15
Eythor Bjornsson, Hannes Helgason, Gisli Halldorsson, Anna Helgadottir, Arnaldur Gylfason, Birte Kehr, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Asmundur Oddsson, Gudmar Thorleifsson, Olafur Th Magnusson, Solveig Gretarsdottir, Florian Zink, Ragnar P Kristjansson, Margret Asgeirsdottir, Dorine W Swinkels, Lambertus A Kiemeney, Gudmundur I Eyjolfsson, Olof Sigurdardottir, Gisli Masson, Isleifur Olafsson, Gudmundur Thorgeirsson, Hilma Holm, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Patrick Sulem, Kari Stefansson
Common sequence variants at the haptoglobin gene (HP) have been associated with lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (β = 0...
April 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28398512/mutant-spastin-proteins-promote-deficits-in-axonal-transport-through-an-isoform-specific-mechanism-involving-casein-kinase-2-activation
#16
Lanfranco Leo, Carina Weissmann, Matthew Burns, Minsu Kang, Yuyu Song, Liang Qiang, Scott T Brady, Peter W Baas, Gerardo Morfini
Mutations of various genes cause hereditary spastic paraplegia (HSP), a neurological disease involving dying-back degeneration of upper motor neurons. From these, mutations in the SPAST gene encoding the microtubule-severing protein spastin account for most HSP cases. Cumulative genetic and experimental evidence suggests that alterations in various intracellular trafficking events, including fast axonal transport (FAT), may contribute to HSP pathogenesis. However, the mechanisms linking SPAST mutations to such deficits remain largely unknown...
April 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28398482/cerkl-gene-knockout-disturbs-photoreceptor-outer-segment-phagocytosis-and-causes-rod-cone-dystrophy-in-zebrafish
#17
Shanshan Yu, Chang Li, Lincoln Biswas, Xuebin Hu, Fei Liu, James Reilly, Xiliang Liu, Ying Liu, Yuwen Huang, Zhaojing Lu, Shanshan Han, Lei Wang, Jing Yu Liu, Tao Jiang, Xinhua Shu, Fulton Wong, Zhaohui Tang, Mugen Liu
In humans, CERKL mutations cause widespread retinal degeneration: early dysfunction and loss of rod and cone photoreceptors in the outer retina and, progressively, death of cells in the inner retina. Despite intensive efforts, the function of CERKL remains obscure and studies in animal models have failed to clarify the disease mechanism of CERKL mutations. To address this gap in knowledge, we have generated a stable CERKL knockout zebrafish model by TALEN technology and a 7bp deletion in CERKL cDNA that caused the premature termination of CERKL...
April 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28398481/mertk-rs4374383-variant-predicts-incident-nonalcoholic-fatty-liver-disease-and-diabetes-role-of-mononuclear-cell-activation-and-adipokine-response-to-dietary-fat
#18
Giovanni Musso, Maurizio Cassader, Franco De Michieli, Elena Paschetta, Silvia Pinach, Francesca Saba, Daria Bongiovanni, Luciana Framarin, Mara Berrutti, Nicola Leone, Stefania Corvisieri, Renato Parente, Federica Molinaro, Antonio Sircana, Simona Bo, Roberto Gambino
No abstract text is available yet for this article.
April 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28398479/clinical-significance-of-mirna-host-gene-promoter-methylation-in-prostate-cancer
#19
Kristina Daniunaite, Monika Dubikaityte, Povilas Gibas, Arnas Bakavicius, Juozas Rimantas Lazutka, Albertas Ulys, Feliksas Jankevicius, Sonata Jarmalaite
Only a part of prostate cancer (PCa) patients has aggressive malignancy requiring adjuvant treatment after radical prostatectomy (RP). Biomarkers capable to predict biochemical PCa recurrence (BCR) after RP would significantly improve preoperative risk stratification and treatment decisions. MicroRNA (miRNA) deregulation has recently emerged as an important phenomenon in tumor development and progression, however, the mechanisms remain largely unstudied. In the present study, based on microarray profiling of DNA methylation in 9 pairs of PCa and noncancerous prostate tissues (NPT), host genes of miR-155-5p, miR-152-3p, miR-137, miR-31-5p, and miR-642a, -b were analyzed for promoter methylation in 129 PCa, 35 NPT, and 17 benign prostatic hyperplasia samples (BPH) and compared to the expression of mature miRNAs and their selected targets (DNMT1, KDM1A, and KDM5B)...
April 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28398475/fat-mass-and-obesity-associated-fto-protein-regulates-adult-neurogenesis
#20
Liping Li, Liqun Zang, Feiran Zhang, Junchen Chen, Hui Shen, Liqi Shu, Feng Liang, Chunyue Feng, Deng Chen, Huikang Tao, Tianlei Xu, Ziyi Li, Yunhee Kang, Hao Wu, Lichun Tang, Pumin Zhang, Peng Jin, Qiang Shu, Xuekun Li
Fat mass and obesity-associated gene (FTO) is a member of the Fe (II)- and oxoglutarate-dependent AlkB dioxygenase family and is linked to both obesity and intellectual disability. The role of FTO in neurodevelopment and neurogenesis, however, remains largely unknown. Here we show that FTO is expressed in adult neural stem cells and neurons and displays dynamic expression during postnatal neurodevelopment. The loss of FTO leads to decreased brain size and body weight. We find that FTO deficiency could reduce the proliferation and neuronal differentiation of adult neural stem cells in vivo, which leads to impaired learning and memory...
April 7, 2017: Human Molecular Genetics
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