14 results on '"Orthmann-Murphy JL"'
Search Results
2. Therapeutic Application of Monoclonal Antibodies in Multiple Sclerosis.
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Orthmann‐Murphy, JL and Calabresi, PA
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THERAPEUTIC use of monoclonal antibodies ,MULTIPLE sclerosis treatment ,INFLAMMATION treatment ,IMMUNOREGULATION ,DISEASE progression - Abstract
Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disorder of the central nervous system (CNS). People with MS typically have a relapsing remitting disease course, with episodic neurological dysfunction corresponding to inflammation in the brain or spinal cord. Some relapsing patients develop a secondary progressive disease course, with accumulation of disability over time, yet other people with MS only experience a primary progressive course. Over the past 20 years, 14 immunomodulatory therapies have been approved in MS in order to reduce the frequency of inflammatory relapses and prevent CNS damage. Of the available types of therapies, the monoclonal antibodies are generally the most effective at dampening MS disease activity. In this review we will discuss the development of effective monoclonal antibody therapies coinciding with a better understanding of the complex immunopathogenesis of MS, both successes and failures, as well as targets for future development that address the mechanisms underlying progressive disease. [ABSTRACT FROM AUTHOR]
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- 2017
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3. Practical Approach to Longitudinal Neurologic Care of Adults With X-Linked Adrenoleukodystrophy and Adrenomyeloneuropathy.
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Kornbluh AB, Baldwin A, Fatemi A, Vanderver A, Adang LA, Van Haren K, Sampson J, Eichler FS, Sadjadi R, Engelen M, and Orthmann-Murphy JL
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Although X-linked adrenoleukodystrophy (ALD) has historically been considered a childhood disease managed by pediatric neurologists, it is one of the most common leukodystrophies diagnosed in adulthood. An increase in both male and female adults reaching diagnosis due to familial cases identified by state newborn screening panels and more widespread use of genetic testing results in a large cohort of presymptomatic or early symptomatic adults. This population is in urgent need of standardized assessments and follow-up care. Adults with ALD/adrenomyeloneuropathy (AMN) may be diagnosed in a variety of ways, including after another family member is identified via genetic testing or newborn screening, presenting for symptomatic evaluation, or following diagnosis with primary adrenal insufficiency. Significant provider, patient, and systems-based barriers prevent adult patients with ALD/AMN from receiving appropriate care, including lack of awareness of the importance of longitudinal neurologic management. Confirmation of and education about the diagnosis should be coordinated in conjunction with a genetic counselor. Routine surveillance for adrenal insufficiency and onset of cerebral ALD (CALD) in men should be performed systematically to avoid preventable morbidity and mortality. While women with ALD do not usually develop cerebral demyelination or adrenal insufficiency, they remain at risk for myeloneuropathy and are no longer considered "carriers." After diagnosis, patients should be connected to the robust support networks, foundations, and research organizations available for ALD/AMN. Core principles of neurologic symptom management parallel those for patients with other etiologies of progressive spastic paraplegia. Appropriate patient candidates for hematopoietic stem cell transplant (HSCT) and other investigational disease-modifying strategies require early identification to achieve optimal outcomes. All patients with ALD/AMN, regardless of sex, age, or symptom severity, benefit from a multidisciplinary approach to longitudinal care spearheaded by the neurologist. This review proposes key strategies for diagnostic confirmation, laboratory and imaging surveillance, approach to symptom management, and guidance for identification of appropriate candidates for HSCT and investigational treatments., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2024
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4. Approaches to diagnosis for individuals with a suspected inherited white matter disorder.
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Helman G, Orthmann-Murphy JL, and Vanderver A
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- Humans, Neonatal Screening methods, Infant, Newborn, White Matter diagnostic imaging, White Matter pathology, Magnetic Resonance Imaging methods, Leukoencephalopathies genetics, Leukoencephalopathies diagnosis, Leukoencephalopathies diagnostic imaging
- Abstract
Leukodystrophies are heritable disorders with white matter abnormalities observed on central nervous system magnetic resonance imaging. Pediatric leukodystrophies have long been known for their classically high, "unsolved" rate. Indeed, these disorders provide a diagnostic dilemma for many clinicians as over 100 genetic disorders alone may present with white matter abnormalities, with this figure not taking into account the substantial number of infectious agents, toxicities, and acquired disorders that may affect the white matter of the brain. Achieving a diagnosis may be the single most important step in the clinical course of a leukodystrophy-affected individual, with important implications for care and quality of life. For certain disorders, prompt recognition can direct therapeutic intervention with significant implications and requires urgent recognition. In this review, we cover newborn screening efforts, standard-of-care testing methodologies, and next generation sequencing approaches that continue to change the landscape of leukodystrophy diagnosis. Early studies have shown that next generation sequencing approaches, particularly exome and now genome sequencing have proven to be powerful in helping resolve many cases that were refractory to a single gene or linkage analysis approach. In addition, other methods are required for cases that remain persistently unsolved after next generation sequencing methods have been used. In the past more than half of affected individuals never achieved an etiologic diagnosis, and when they did, the reported times to diagnosis were >5 years although molecular testing has allowed this to be reduced to closer to 16 months. For affected families, next generation sequencing technologies have finally provided a way to fill gaps in diagnosis., Competing Interests: Conflicts of Interest A.V. receives grant or scientific research support from the NINDS, NCATS, Eli Lilly, Biogen, Illumina, Takeda, Homology, SynaptixBio, PMD Foundation. She serves as a scientific advisor without personal compensation to Passage Bio, Orchard therapeutics, Eli Lilly, Biogen, Takeda, ULF, ELA, Yaya Foundation, Affina Therapeutics. Otherwise, the authors report no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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5. Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource.
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Koch RL, Soler-Alfonso C, Kiely BT, Asai A, Smith AL, Bali DS, Kang PB, Landstrom AP, Akman HO, Burrow TA, Orthmann-Murphy JL, Goldman DS, Pendyal S, El-Gharbawy AH, Austin SL, Case LE, Schiffmann R, Hirano M, and Kishnani PS
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- Child, Preschool, Humans, Glycogen, Glycogen Storage Disease Type IV diagnosis, Glycogen Storage Disease Type IV genetics, Glycogen Storage Disease Type IV therapy, Neurodegenerative Diseases, Glycogen Storage Disease diagnosis, Glycogen Storage Disease genetics, Glycogen Storage Disease therapy
- Abstract
Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disorder caused by pathogenic variants in GBE1 which results in reduced or deficient glycogen branching enzyme activity. Consequently, glycogen synthesis is impaired and leads to accumulation of poorly branched glycogen known as polyglucosan. GSD IV is characterized by a remarkable degree of phenotypic heterogeneity with presentations in utero, during infancy, early childhood, adolescence, or middle to late adulthood. The clinical continuum encompasses hepatic, cardiac, muscular, and neurologic manifestations that range in severity. The adult-onset form of GSD IV, referred to as adult polyglucosan body disease (APBD), is a neurodegenerative disease characterized by neurogenic bladder, spastic paraparesis, and peripheral neuropathy. There are currently no consensus guidelines for the diagnosis and management of these patients, resulting in high rates of misdiagnosis, delayed diagnosis, and lack of standardized clinical care. To address this, a group of experts from the United States developed a set of recommendations for the diagnosis and management of all clinical phenotypes of GSD IV, including APBD, to support clinicians and caregivers who provide long-term care for individuals with GSD IV. The educational resource includes practical steps to confirm a GSD IV diagnosis and best practices for medical management, including (a) imaging of the liver, heart, skeletal muscle, brain, and spine, (b) functional and neuromusculoskeletal assessments, (c) laboratory investigations, (d) liver and heart transplantation, and (e) long-term follow-up care. Remaining knowledge gaps are detailed to emphasize areas for improvement and future research., (Published by Elsevier Inc.)
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- 2023
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6. The utility of whole exome sequencing in diagnosing neurological disorders in adults from a highly consanguineous population.
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Mu W, Schiess N, Orthmann-Murphy JL, and El-Hattab AW
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- Adolescent, Adult, Female, Humans, Male, Middle Aged, Retrospective Studies, Young Adult, Consanguinity, Nervous System Diseases diagnosis, Nervous System Diseases genetics, Exome Sequencing methods
- Abstract
There is increasing evidence that whole exome sequencing (WES) has a high diagnostic yield and is cost-efficient for individuals with neurological phenotypes. However, there is limited data on the use of WES in non-Western populations, including populations with a high rate of consanguinity. Retrospective chart review was performed on 24 adults with undiagnosed neurological symptoms evaluated in genetics and neurology clinics in a tertiary care facility on the Arabian Peninsula, and had WES between 2014 and 2016. Definitive diagnoses were made in 13/24 (54%) of cases. Of these, 5/13 (38%) revealed novel pathogenic variants. Of the known 19/24 (79%) consanguineous cases, diagnostic rate was slightly higher, 11/19 (58%) as compared to 2/5 (40%) among non-consanguineous cases. Autosomal recessive disorders comprised 10/13 (77%) of molecular diagnoses, all found to be due to homozygous pathogenic variants among consanguineous cases. WES in this cohort of adults with neurological symptoms had a high diagnostic rate likely due to high consanguinity rates in this population, as evidenced by the high diagnostic rate of homozygous pathogenic variants.
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- 2019
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7. Myelin remodeling through experience-dependent oligodendrogenesis in the adult somatosensory cortex.
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Hughes EG, Orthmann-Murphy JL, Langseth AJ, and Bergles DE
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- Aging physiology, Animals, Animals, Newborn, Axons physiology, Brain growth & development, Brain physiology, Environment, Female, Male, Mice, Neuronal Plasticity physiology, Photic Stimulation, Sensory Deprivation, Stem Cells, Myelin Sheath physiology, Neurogenesis physiology, Oligodendroglia physiology, Sensation physiology, Somatosensory Cortex physiology
- Abstract
Oligodendrocyte generation in the adult CNS provides a means to adapt the properties of circuits to changes in life experience. However, little is known about the dynamics of oligodendrocytes and the extent of myelin remodeling in the mature brain. Using longitudinal in vivo two-photon imaging of oligodendrocytes and their progenitors in the mouse cerebral cortex, we show that myelination is an inefficient and extended process, with half of the final complement of oligodendrocytes generated after 4 months of age. Oligodendrocytes that successfully integrated formed new sheaths on unmyelinated and sparsely myelinated axons, and they were extremely stable, gradually changing the pattern of myelination. Sensory enrichment robustly increased oligodendrocyte integration, but did not change the length of existing sheaths. This experience-dependent enhancement of myelination in the mature cortex may accelerate information transfer in these circuits and strengthen the ability of axons to sustain activity by providing additional metabolic support.
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- 2018
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8. Lineage tracing reveals dynamic changes in oligodendrocyte precursor cells following cuprizone-induced demyelination.
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Baxi EG, DeBruin J, Jin J, Strasburger HJ, Smith MD, Orthmann-Murphy JL, Schott JT, Fairchild AN, Bergles DE, and Calabresi PA
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- Age Factors, Animals, Autophagy-Related Proteins, Bacterial Proteins genetics, Bacterial Proteins metabolism, Cell Differentiation genetics, Cell Lineage drug effects, Cell Lineage genetics, Corpus Callosum drug effects, Corpus Callosum pathology, Disease Models, Animal, Hippocampus drug effects, Hippocampus pathology, Intracellular Signaling Peptides and Proteins metabolism, Luminescent Proteins genetics, Luminescent Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, RNA, Untranslated genetics, RNA, Untranslated metabolism, Receptor, Platelet-Derived Growth Factor alpha genetics, Receptor, Platelet-Derived Growth Factor alpha metabolism, Remyelination drug effects, Remyelination physiology, Cuprizone toxicity, Demyelinating Diseases chemically induced, Demyelinating Diseases pathology, Monoamine Oxidase Inhibitors toxicity, Oligodendrocyte Precursor Cells drug effects
- Abstract
The regeneration of oligodendrocytes is a crucial step in recovery from demyelination, as surviving oligodendrocytes exhibit limited structural plasticity and rarely form additional myelin sheaths. New oligodendrocytes arise through the differentiation of platelet-derived growth factor receptor α (PDGFRα) expressing oligodendrocyte progenitor cells (OPCs) that are widely distributed throughout the CNS. Although there has been detailed investigation of the behavior of these progenitors in white matter, recent studies suggest that disease burden in multiple sclerosis (MS) is more strongly correlated with gray matter atrophy. The timing and efficiency of remyelination in gray matter is distinct from white matter, but the dynamics of OPCs that contribute to these differences have not been defined. Here, we used in vivo genetic fate tracing to determine the behavior of OPCs in gray and white matter regions in response to cuprizone-induced demyelination. Our studies indicate that the temporal dynamics of OPC differentiation varies significantly between white and gray matter. While OPCs rapidly repopulate the corpus callosum and mature into CC1 expressing mature oligodendrocytes, OPC differentiation in the cingulate cortex and hippocampus occurs much more slowly, resulting in a delay in remyelination relative to the corpus callosum. The protracted maturation of OPCs in gray matter may contribute to greater axonal pathology and disease burden in MS., (© 2017 Wiley Periodicals, Inc.)
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- 2017
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9. Clinical Reasoning: A 70-year-old woman with acute-onset weakness and progressive hemiataxia.
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Schreck KC, Orthmann-Murphy JL, and Newsome SD
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- Aged, Antibodies blood, Diabetes Mellitus, Type 2 complications, Female, Glutamate Decarboxylase immunology, Humans, Muscle Weakness diagnostic imaging, Cerebellar Ataxia complications, Cerebellar Ataxia diagnosis, Muscle Weakness etiology
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- 2016
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10. A 6-Year-Old With Leg Cramps.
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Jenssen BP, Lautz AJ, Orthmann-Murphy JL, Yum SW, Waanders A, and Fox E
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- Child, Female, Humans, Leg, Muscle Cramp etiology, Myokymia etiology, Neuroblastoma complications, Paraneoplastic Syndromes, Nervous System complications, Neuroblastoma diagnosis, Paraneoplastic Syndromes, Nervous System diagnosis
- Abstract
A 6-year-old girl presented with a history of leg pain and cramping that progressively worsened over a 2- to 3-week period of time. Her examination was notable for normal vital signs, limited range of motion of her left hip, and a limp. Inflammatory markers were slightly elevated, but the serum electrolytes, calcium, and magnesium, complete blood cell count and differential, and creatine kinase level were normal. She was hospitalized for further diagnostic evaluation and was noted to have abnormal muscle movements classified as myokymia (continuous involuntary quivering, rippling, or undulating movement of muscles). Electromyography confirmed the myokymia but did not reveal evidence of a myopathy or neuropathy, prompting additional evaluation for a systemic etiology., (Copyright © 2015 by the American Academy of Pediatrics.)
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- 2015
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11. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.
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Orthmann-Murphy JL, Salsano E, Abrams CK, Bizzi A, Uziel G, Freidin MM, Lamantea E, Zeviani M, Scherer SS, and Pareyson D
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- Adult, Brain pathology, Connexin 43 genetics, Connexin 43 metabolism, Connexins metabolism, Evoked Potentials, Female, HeLa Cells, Humans, Magnetic Resonance Imaging, Male, Microscopy, Fluorescence, Middle Aged, Patch-Clamp Techniques, Pedigree, Phenotype, Spastic Paraplegia, Hereditary metabolism, Spastic Paraplegia, Hereditary pathology, Connexins genetics, Mutation, Spastic Paraplegia, Hereditary genetics
- Abstract
Recessive mutations in GJA12/GJC2, the gene that encodes the gap junction protein connexin47 (Cx47), cause Pelizaeus-Merzbacher-like disease (PMLD), an early onset dysmyelinating disorder of the CNS, characterized by nystagmus, psychomotor delay, progressive spasticity and cerebellar signs. Here we describe three patients from one family with a novel recessively inherited mutation, 99C>G (predicted to cause an Ile>Met amino acid substitution; I33M) that causes a milder phenotype. All three had a late-onset, slowly progressive, complicated spastic paraplegia, with normal or near-normal psychomotor development, preserved walking capability through adulthood, and no nystagmus. MRI and MR spectroscopy imaging were consistent with a hypomyelinating leukoencephalopathy. The mutant protein forms gap junction plaques at cell borders similar to wild-type (WT) Cx47 in transfected cells, but fails to form functional homotypic channels in scrape-loading and dual whole-cell patch clamp assays. I33M forms overlapping gap junction plaques and functional channels with Cx43, however, I33M/Cx43 channels open only when a large voltage difference is applied to paired cells. These channels probably do not function under physiological conditions, suggesting that Cx47/Cx43 channels between astrocytes and oligodendrocytes are disrupted, similar to the loss-of-function endoplasmic reticulum-retained Cx47 mutants that cause PMLD. Thus, GJA12/GJC2 mutations can result in a milder phenotype than previously appreciated, but whether I33M retains a function of Cx47 not directly related to forming functional gap junction channels is not known.
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- 2009
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12. Gap junctions couple astrocytes and oligodendrocytes.
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Orthmann-Murphy JL, Abrams CK, and Scherer SS
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- Animals, Astrocytes cytology, Axons metabolism, Axons ultrastructure, Buffers, Gap Junctions ultrastructure, Humans, Models, Molecular, Myelin Sheath metabolism, Oligodendroglia cytology, Potassium metabolism, Protein Conformation, Protein Isoforms chemistry, Protein Isoforms genetics, Protein Isoforms metabolism, Astrocytes metabolism, Connexins chemistry, Connexins genetics, Connexins metabolism, Gap Junctions metabolism, Oligodendroglia metabolism
- Abstract
In vertebrates, a family of related proteins called connexins form gap junctions (GJs), which are intercellular channels. In the central nervous system (CNS), GJs couple oligodendrocytes and astrocytes (O/A junctions) and adjacent astrocytes (A/A junctions), but not adjacent oligodendrocytes, forming a "glial syncytium." Oligodendrocytes and astrocytes each express different connexins. Mutations of these connexin genes demonstrate that the proper functioning of myelin and oligodendrocytes requires the expression of these connexins. The physiological function of O/A and A/A junctions, however, remains to be illuminated.
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- 2008
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13. Two distinct heterotypic channels mediate gap junction coupling between astrocyte and oligodendrocyte connexins.
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Orthmann-Murphy JL, Freidin M, Fischer E, Scherer SS, and Abrams CK
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- Astrocytes metabolism, Connexins chemistry, Gap Junctions chemistry, Gap Junctions physiology, HeLa Cells, Humans, Ion Channel Gating physiology, Ion Channels chemistry, Oligodendroglia metabolism, Astrocytes physiology, Connexins physiology, Gap Junctions metabolism, Ion Channels physiology, Oligodendroglia physiology
- Abstract
Genetic diseases demonstrate that the normal function of CNS myelin depends on connexin32 (Cx32) and Cx47, gap junction (GJ) proteins expressed by oligodendrocytes. GJs couple oligodendrocytes and astrocytes (O/A channels) as well as astrocytes themselves (A/A channels). Because astrocytes express different connexins (Cx30 and Cx43), O/A channels must be heterotypic, whereas A/A channels may be homotypic or heterotypic. Using electrophysiological and immunocytochemical approaches, we found that Cx47/Cx43 and Cx32/Cx30 efficiently formed functional channels, but other potential heterotypic O/A and A/A pairs did not. These results suggest that Cx30/Cx30 and Cx43/Cx43 channels mediate A/A coupling, and Cx47/Cx43 and Cx32/Cx30 channels mediate O/A coupling. Furthermore, Cx47/Cx43 and Cx32/Cx30 channels have distinct macroscopic and single-channel properties and different dye permeabilities. Finally, Cx47 mutants that cause Pelizaeus-Merzbacher-like disease do not efficiently form functional channels with Cx43, indicating that disrupted Cx47/Cx43 channels cause this disease.
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- 2007
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14. Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease.
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Orthmann-Murphy JL, Enriquez AD, Abrams CK, and Scherer SS
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- Amino Acid Sequence, Animals, Astrocytes metabolism, Blotting, Western, Brain metabolism, Endoplasmic Reticulum metabolism, Gap Junctions metabolism, HeLa Cells, Humans, Immunohistochemistry, Macaca mulatta, Molecular Sequence Data, Mutation, Oligodendroglia metabolism, Patch-Clamp Techniques, Polymerase Chain Reaction, Transfection, Cell Communication genetics, Connexins genetics, Gap Junctions genetics, Pelizaeus-Merzbacher Disease genetics
- Abstract
Recessive mutations in GJA12/Cx47, the gene encoding the gap junction protein connexin47 (Cx47), cause Pelizaeus-Merzbacher-like disease (PMLD), which is characterized by severe CNS dysmyelination. Three missense PMLD mutations, P87S, Y269D and M283T, were expressed in communication-incompetent HeLa cells, and in each case the mutant proteins appeared to at least partially accumulate in the ER. Cells expressing each mutant did not pass Lucifer Yellow or neurobiotin in scrape loading assays, in contrast to robust transfer in cells expressing wild type Cx47. Dual whole-cell patch clamping of transfected Neuro2A cells demonstrated that none of the mutants formed functional channels, in contrast to wild type Cx47. Immunostaining sections of primate brains demonstrated that oligodendrocytes express Cx47, which is primarily localized to their cell bodies. Thus, the Cx47 mutants associated with PMLD likely disrupt the gap junction coupling between astrocytes and oligodendrocytes.
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- 2007
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