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https://www.readbyqxmd.com/read/28467418/a-kcnc3-mutation-causes-a-neurodevelopmental-non-progressive-sca13-subtype-associated-with-dominant-negative-effects-and-aberrant-egfr-trafficking
#1
Swati Khare, Jerelyn A Nick, Yalan Zhang, Kira Galeano, Brittany Butler, Habibeh Khoshbouei, Sruti Rayaprolu, Tyisha Hathorn, Laura P W Ranum, Lisa Smithson, Todd E Golde, Martin Paucar, Richard Morse, Michael Raff, Julie Simon, Magnus Nordenskjöld, Karin Wirdefeldt, Diego E Rincon-Limas, Jada Lewis, Leonard K Kaczmarek, Pedro Fernandez-Funez, Harry S Nick, Michael F Waters
The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3...
2017: PloS One
https://www.readbyqxmd.com/read/28444220/a-panel-study-on-patients-with-dominant-cerebellar-ataxia-highlights-the-frequency-of-channelopathies
#2
Marie Coutelier, Giulia Coarelli, Marie-Lorraine Monin, Juliette Konop, Claire-Sophie Davoine, Christelle Tesson, Rémi Valter, Mathieu Anheim, Anthony Behin, Giovanni Castelnovo, Perrine Charles, Albert David, Claire Ewenczyk, Mélanie Fradin, Cyril Goizet, Didier Hannequin, Pierre Labauge, Florence Riant, Pierre Sarda, Yves Sznajer, François Tison, Urielle Ullmann, Lionel Van Maldergem, Fanny Mochel, Alexis Brice, Giovanni Stevanin, Alexandra Durr
Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype-phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more 'conventional' ataxias...
June 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28388656/integrated-network-analysis-reveals-potentially-novel-molecular-mechanisms-and-therapeutic-targets-of-refractory-epilepsies
#3
Hongwei Chu, Pin Sun, Jiahui Yin, Guangming Liu, Yiwei Wang, Pengyao Zhao, Yizhun Zhu, Xiaohan Yang, Tiezheng Zheng, Xuezhong Zhou, Weilin Jin, Changkai Sun
Epilepsy is a complex neurological disorder and a significant health problem. The pathogenesis of epilepsy remains obscure in a significant number of patients and the current treatment options are not adequate in about a third of individuals which were known as refractory epilepsies (RE). Network medicine provides an effective approach for studying the molecular mechanisms underlying complex diseases. Here we integrated 1876 disease-gene associations of RE and located those genes to human protein-protein interaction (PPI) network to obtain 42 significant RE-associated disease modules...
2017: PloS One
https://www.readbyqxmd.com/read/27750143/exploring-the-neural-mechanisms-of-finasteride-a-proteomic-analysis-in-the-nucleus-accumbens
#4
Alessio Soggiu, Cristian Piras, Viviana Greco, Paola Devoto, Andrea Urbani, Luigino Calzetta, Marco Bortolato, Paola Roncada
The enzyme 5α-reductase (5αR) catalyzes the conversion of progesterone and testosterone into neuroactive steroids implicated in a wide array of behavioral functions. The prototypical 5αR inhibitor, finasteride (FIN), is clinically approved for the treatment of androgenic alopecia and benign prostatic hyperplasia. Recent evidence has shown that FIN, albeit generally well tolerated, can induce untoward psychological effects in a subset of patients; furthermore, this drug may have therapeutic efficacy for a number of different neuropsychiatric conditions, ranging from Tourette syndrome to schizophrenia...
December 2016: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/27730449/integrated-transcriptome-analysis-of-human-ips-cells-derived-from-a-fragile-x-syndrome-patient-during-neuronal-differentiation
#5
Ping Lu, Xiaolong Chen, Yun Feng, Qiao Zeng, Cizhong Jiang, Xianmin Zhu, Guoping Fan, Zhigang Xue
Fragile X syndrome (FXS) patients carry the expansion of over 200 CGG repeats at the promoter of fragile X mental retardation 1 (FMR1), leading to decreased or absent expression of its encoded fragile X mental retardation protein (FMRP). However, the global transcriptional alteration by FMRP deficiency has not been well characterized at single nucleotide resolution, i.e., RNA-seq. Here, we performed in-vitro neuronal differentiation of human induced pluripotent stem (iPS) cells that were derived from fibroblasts of a FXS patient (FXS-iPSC)...
November 2016: Science China. Life Sciences
https://www.readbyqxmd.com/read/27397082/immunoproteomic-studies-on-paediatric-opsoclonus-myoclonus-associated-with-neuroblastoma
#6
Estefanía Torres-Vega, María Durán-Moreno, Manuel Sánchez Del Pino, Yania Yáñez, Adela Cañete, Victoria Castel, Rogelio López-Cuevas, Juan Jesús Vílchez, Josep Dalmau, Francesc Graus, José Manuel García Verdugo, Luis Bataller
We aimed to identify new cell-membrane antigens implicated in opsoclonus-myoclonus with neuroblastoma. The sera of 3 out of 14 patients showed IgG electron-microscopy immunogold reactivity on SH-SY5Y neuroblastoma cells. Immunoprecipitation experiments using rat brain synaptosomes and SH-SY5Y cells led to the identification of: (1) thirty-one nuclear/cytoplasmic proteins (including antigens HuB, HuC); (2) seven neuronal membrane proteins, including the Shaw-potassium channel Kv3.3 (KCNC3), whose genetic disruption in mice causes ataxia and generalized muscle twitching...
August 15, 2016: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/27062503/mutations-in-the-irbit-domain-of-itpr1-are-a-frequent-cause-of-autosomal-dominant-nonprogressive-congenital-ataxia
#7
S Barresi, M Niceta, P Alfieri, V Brankovic, G Piccini, A Bruselles, M R Barone, R Cusmai, M Tartaglia, E Bertini, G Zanni
Congenital ataxias are nonprogressive neurological disorders characterized by neonatal hypotonia, developmental delay and ataxia, variably associated with intellectual disability and other neurological or extraneurological features. We performed trio-based whole-exome sequencing of 12 families with congenital cerebellar and/or vermis atrophy in parallel with targeted next-generation sequencing of known ataxia genes (CACNA1A, ITPR1, KCNC3, ATP2B3 and GRM1) in 12 additional patients with a similar phenotype. Novel pathological mutations of ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) were found in seven patients from four families (4/24, ∼16...
January 2017: Clinical Genetics
https://www.readbyqxmd.com/read/26997484/kv3-3-channels-bind-hax-1-and-arp2-3-to-assemble-a-stable-local-actin-network-that-regulates-channel-gating
#8
Yalan Zhang, Xiao-Feng Zhang, Matthew R Fleming, Anahita Amiri, Lynda El-Hassar, Alexei A Surguchev, Callen Hyland, David P Jenkins, Rooma Desai, Maile R Brown, Valeswara-Rao Gazula, Michael F Waters, Charles H Large, Tamas L Horvath, Dhasakumar Navaratnam, Flora M Vaccarino, Paul Forscher, Leonard K Kaczmarek
Mutations in the Kv3.3 potassium channel (KCNC3) cause cerebellar neurodegeneration and impair auditory processing. The cytoplasmic C terminus of Kv3.3 contains a proline-rich domain conserved in proteins that activate actin nucleation through Arp2/3. We found that Kv3.3 recruits Arp2/3 to the plasma membrane, resulting in formation of a relatively stable cortical actin filament network resistant to cytochalasin D that inhibits fast barbed end actin assembly. These Kv3.3-associated actin structures are required to prevent very rapid N-type channel inactivation during short depolarizations of the plasma membrane...
April 7, 2016: Cell
https://www.readbyqxmd.com/read/26677414/spinocerebellar-ataxia-28-a-novel-afg3l2-mutation-in-a-german-family-with-young-onset-slow-progression-and-saccadic-slowing
#9
Christine Zühlke, Barbara Mikat, Dagmar Timmann, Dagmar Wieczorek, Gabriele Gillessen-Kaesbach, Katrin Bürk
BACKGROUND: Spinocerebellar ataxia type 28 (SCA28) is related to mutations of the ATPase family gene 3-like 2 gene (AFG3L2). To date, 13 private missense mutations have been identified in families of French, Italian, and German ancestry, but overall, the disorder seems to be rare in Europe. Here, we report a kindred of German ancestry with four affected family members presenting with slowly progressive ataxia, mild pyramidal tract signs and slow saccades. METHODS: After excluding repeat expansions in the genes for SCA1-3, 6-8, 10, 12, and 17, Sanger sequencing of the coding regions of TTBK2 (SCA11), KCNC3 (SCA13), PRKCG (SCA14), FGF14 (SCA27) and AFG3L2 (SCA28) was performed...
2015: Cerebellum & Ataxias
https://www.readbyqxmd.com/read/26442672/kv3-3-potassium-channels-and-spinocerebellar-ataxia
#10
Yalan Zhang, Leonard K Kaczmarek
The voltage-dependent potassium channel subunit Kv3.3 is expressed at high levels in cerebellar Purkinje cells, in auditory brainstem nuclei and in many other neurons capable of firing at high rates. In the cerebellum, it helps to shape the very characteristic complex spike of Purkinje cells. Kv3.3 differs from other closely related channels in that human mutations in the gene encoding Kv3.3 (KCNC3) result in a unique neurodegenerative disease termed spinocerebellar ataxia type 13 (SCA13). This primarily affects the cerebellum, but also results in extracerebellar symptoms...
August 15, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/25981959/de-novo-point-mutations-in-patients-diagnosed-with-ataxic-cerebral-palsy
#11
Ricardo Parolin Schnekenberg, Emma M Perkins, Jack W Miller, Wayne I L Davies, Maria Cristina D'Adamo, Mauro Pessia, Katherine A Fawcett, David Sims, Elodie Gillard, Karl Hudspith, Paul Skehel, Jonathan Williams, Mary O'Regan, Sandeep Jayawant, Rosalind Jefferson, Sarah Hughes, Andrea Lustenberger, Jiannis Ragoussis, Mandy Jackson, Stephen J Tucker, Andrea H Németh
Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2...
July 2015: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/25756792/functional-analysis-helps-to-define-kcnc3-mutational-spectrum-in-dutch-ataxia-cases
#12
Anna Duarri, Esther A R Nibbeling, Michiel R Fokkens, Michel Meijer, Melissa Boerrigter, Corien C Verschuuren-Bemelmans, Berry P H Kremer, Bart P van de Warrenburg, Dennis Dooijes, Erik Boddeke, Richard J Sinke, Dineke S Verbeek
Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominantly inherited neurodegenerative disorder of the cerebellum caused by mutations in the voltage gated potassium channel KCNC3. To identify novel pathogenic SCA13 mutations in KCNC3 and to gain insights into the disease prevalence in the Netherlands, we sequenced the entire coding region of KCNC3 in 848 Dutch cerebellar ataxia patients with familial or sporadic origin. We evaluated the pathogenicity of the identified variants by co-segregation analysis and in silico prediction followed by biochemical and electrophysiological studies...
2015: PloS One
https://www.readbyqxmd.com/read/25315682/deficiency-of-the-mir-29a-b-1-cluster-leads-to-ataxic-features-and-cerebellar-alterations-in-mice
#13
Aikaterini S Papadopoulou, Lutgarde Serneels, Tilmann Achsel, Wim Mandemakers, Zsuzsanna Callaerts-Vegh, James Dooley, Pierre Lau, Torik Ayoubi, Enrico Radaelli, Marco Spinazzi, Melanie Neumann, Sébastien S Hébert, Asli Silahtaroglu, Adrian Liston, Rudi D'Hooge, Markus Glatzel, Bart De Strooper
miR-29 is expressed strongly in the brain and alterations in expression have been linked to several neurological disorders. To further explore the function of this miRNA in the brain, we generated miR-29a/b-1 knockout animals. Knockout mice develop a progressive disorder characterized by locomotor impairment and ataxia. The different members of the miR-29 family are strongly expressed in neurons of the olfactory bulb, the hippocampus and in the Purkinje cells of the cerebellum. Morphological analysis showed that Purkinje cells are smaller and display less dendritic arborisation compared to their wildtype littermates...
January 2015: Neurobiology of Disease
https://www.readbyqxmd.com/read/25152487/kcnc3-r420h-a-k-channel-mutation-causative-in-spinocerebellar-ataxia-13-displays-aberrant-intracellular-trafficking
#14
Carolina Gallego-Iradi, Justin S Bickford, Swati Khare, Alexis Hall, Jerelyn A Nick, Donya Salmasinia, Kolja Wawrowsky, Serguei Bannykh, Duong P Huynh, Diego E Rincon-Limas, Stefan M Pulst, Harry S Nick, Pedro Fernandez-Funez, Michael F Waters
Spinocerebellar ataxia 13 (SCA13) is an autosomal dominant disease resulting from mutations in KCNC3 (Kv3.3), a voltage-gated potassium channel. The KCNC3(R420H) mutation was first identified as causative for SCA13 in a four-generation Filipino kindred with over 20 affected individuals. Electrophysiological analyses in oocytes previously showed that this mutation did not lead to a functional channel and displayed a dominant negative phenotype. In an effort to identify the molecular basis of this allelic form of SCA13, we first determined that human KCNC3(WT) and KCNC3(R420H) display disparate post-translational modifications, and the mutant protein has reduced complex glycan adducts...
November 2014: Neurobiology of Disease
https://www.readbyqxmd.com/read/24418349/blood-expression-profiles-of-fragile-x-premutation-carriers-identify-candidate-genes-involved-in-neurodegenerative-and-infertility-phenotypes
#15
Elisabet Mateu-Huertas, Laia Rodriguez-Revenga, Maria Isabel Alvarez-Mora, Irene Madrigal, Rob Willemsen, Montserrat Milà, Eulàlia Martí, Xavier Estivill
Male premutation carriers presenting between 55 and 200 CGG repeats in the Fragile-X-associated (FMR1) gene are at risk of developing Fragile X Tremor/Ataxia Syndrome (FXTAS), and females undergo Premature Ovarian Failure (POF1). Here, we have evaluated gene expression profiles from blood in male FMR1 premutation carriers and detected a strong deregulation of genes enriched in FXTAS relevant biological pathways, including inflammation, neuronal homeostasis and viability. Gene expression profiling distinguished between control individuals, carriers with FXTAS and carriers without FXTAS, with levels of expanded FMR1 mRNA being increased in FXTAS patients...
May 2014: Neurobiology of Disease
https://www.readbyqxmd.com/read/24372385/a-subset-of-genomic-alterations-detected-in-rolandic-epilepsies-contains-candidate-or-known-epilepsy-genes-including-grin2a-and-prrt2
#16
Sarra Dimassi, Audrey Labalme, Gaetan Lesca, Gabrielle Rudolf, Nadine Bruneau, Edouard Hirsch, Alexis Arzimanoglou, Jacques Motte, Anne de Saint Martin, Nadia Boutry-Kryza, Robin Cloarec, Afaf Benitto, Agnès Ameil, Patrick Edery, Philippe Ryvlin, Julitta De Bellescize, Pierre Szepetowski, Damien Sanlaville
OBJECTIVES: Rolandic epilepsies (REs) represent the most frequent epilepsy in childhood. Patients may experience cognitive, speech, language, reading, and behavioral issues. The genetic origin of REs has long been debated. The participation of rare copy number variations (CNVs) in the pathophysiology of various human epilepsies has been increasingly recognized. However, no systematic search for microdeletions or microduplications has been reported in RE so far. METHODS: Array comparative genomic hybridization (aCGH) and quantitative polymerase chain reaction (qPCR) were used to analyze the genomic status of a series of 47 unrelated RE patients who displayed various types of electroclinical manifestations...
February 2014: Epilepsia
https://www.readbyqxmd.com/read/24030952/next-generation-sequencing-for-molecular-diagnosis-of-neurological-disorders-using-ataxias-as-a-model
#17
Andrea H Németh, Alexandra C Kwasniewska, Stefano Lise, Ricardo Parolin Schnekenberg, Esther B E Becker, Katarzyna D Bera, Morag E Shanks, Lorna Gregory, David Buck, M Zameel Cader, Kevin Talbot, Rajith de Silva, Nicholas Fletcher, Rob Hastings, Sandeep Jayawant, Patrick J Morrison, Paul Worth, Malcolm Taylor, John Tolmie, Mary O'Regan, Ruth Valentine, Emily Packham, Julie Evans, Anneke Seller, Jiannis Ragoussis
Many neurological conditions are caused by immensely heterogeneous gene mutations. The diagnostic process is often long and complex with most patients undergoing multiple invasive and costly investigations without ever reaching a conclusive molecular diagnosis. The advent of massively parallel, next-generation sequencing promises to revolutionize genetic testing and shorten the 'diagnostic odyssey' for many of these patients. We performed a pilot study using heterogeneous ataxias as a model neurogenetic disorder to assess the introduction of next-generation sequencing into clinical practice...
October 2013: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/23293936/spinocerebellar-ataxia-type-13-is-an-uncommon-sca-subtype-in-the-chinese-han-population
#18
Lan Peng, Chunrong Wang, Zhao Chen, Jun-Ling Wang, Bei-Sha Tang, Hong Jiang
The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders, among which SCA subtype 13 (SCA13) was found associated with mutations in the KCNC3 gene. Among 522 Chinese Han SCA patients (including familial and sporadic) we have collected since 1995, approximately 40% of them have not yet been assigned genotype. To investigate the mutation frequency of KCNC3 in SCA patients from mainland Chinese Han population, we analyzed the KCNC3 gene in 201 unrelated patients diagnosed with dominantly inherited cerebellar ataxia using the denaturing high-performance liquid chromatography (DHPLC) method...
July 2013: International Journal of Neuroscience
https://www.readbyqxmd.com/read/23215817/mesial-temporal-lobe-epilepsy-in-a-patient-with-spinocerebellar-ataxia-type-13-sca13
#19
Katrin Bürk, Adam Strzelczyk, Philipp S Reif, Karla P Figueroa, Stefan M Pulst, Christine Zühlke, Wolfgang H Oertel, Hajo M Hamer, Felix Rosenow
We report a female patient of German descent with a molecular diagnosis of SCA13 who presented with a history of cerebellar ataxia and epilepsy. The underlying mutation R420H had been shown to cause a dominant negative effect on the functional properties of the voltage-gated potassium channel KCNC3. Despite widespread KCNC3 expression in the central nervous system, the patient presented with a left mesiotemporal electroencephalogram focus and left hippocampal sclerosis. This is the first case, which reports an association between mesial temporal lobe epilepsy and spinocerebellar ataxia type 13...
April 2013: International Journal of Neuroscience
https://www.readbyqxmd.com/read/22977489/whole-rat-dna-array-survey-for-candidate-genes-related-to-hypertension-in-kidneys-from-three-spontaneously-hypertensive-rat-substrains-at-two-stages-of-age-and-with-hypotensive-induction-caused-by-hydralazine-hydrochloride
#20
Kosho Kinoshita, Mohammad Said Ashenagar, Masaki Tabuchi, Hideaki Higashino
Clarification of the genetic nature and more effective care for hypertension are required, given the high incidences of cardiovascular and cerebrovascular mortality. Thus, we surveyed candidate genes for hypertension with rat whole gene DNA microarrays using three novel methods. Gene expression analyses were conducted as follows: Method 1, three types of spontaneously hypertensive rat (SHR) substrains, SHR, stroke-prone SHR (SHRSP) and malignant type of SHRSP (M-SHRSP) were used and compared to normotensive Wistar Kyoto rats; Method 2, the expressed genes between rats of different ages were compared for different blood pressures; and Method 3, genes that were expressed in rats treated with or without an acute hypotensive stimulus, the antihypertensive hydralazine hydrochloride, were compared...
March 2011: Experimental and Therapeutic Medicine
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