DOCSLIB.ORG

The CNS Phenotype of X-Linked Charcot-Marie-Tooth Disease More Than a Peripheral Problem

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The CNS Phenotype of X-Linked Charcot-Marie-Tooth Disease More Than a Peripheral Problem Views & Reviews CME The CNS phenotype of X-linked Charcot-Marie-Tooth disease More than a peripheral problem Robert A. Taylor, MD; Erin M. Simon, MD; Harold G. Marks, MD; and Steven S. Scherer, MD, PhD X-linked Charcot-Marie-Tooth disease (CMTX) is the lasting 4 hours. The following day, he developed the second most common form of inherited demyelinat- same symptoms, and mild right leg weakness, last- ing neuropathy, next to CMT type 1A, which is ing 10 hours. On day 3, he developed a complete caused by duplication of the PMP22 gene.1 CMTX is motor aphasia, right arm weakness, dysphagia, and caused by mutations in GJB1, the gene encoding loss of gag reflex, lasting 4 hours. MRI (on day 3) connexin32 (Cx32), which belongs to a highly con- showed abnormally increased T2 signal and reduced served family of proteins that form gap junctions in diffusion in the posterior portion of the centrum vertebrates. Myelinating Schwann cells express semiovale bilaterally (figure 1, A and B), as well as Cx32, which likely forms gap junctions between the in the splenium of the corpus callosum (figure 1, C layers of the myelin sheath, thereby providing a and D). These lesions spared the subcortical U fibers shorter pathway for the diffusion of small molecules and did not enhance (not shown). Three-dimensional and ions directly across the myelin sheath.2 Oligo- time-of-flight MR angiography of the intracranial dendrocytes also express Cx32, which participates in vessels, electroencephalography, and CSF were nor- the gap junction coupling of oligodendrocytes and mal, including a normal lactate level (1.1 mmol/L) astrocytes.3 and no oligoclonal bands. Laboratory tests, including More than 240 different GJB1 mutations have complete blood count, electrolytes, renal function, co- been described (http://molgen-www.uia.ac.be/CMT- agulation parameters, urinalysis, and urine toxicol- Mutations/DataSource/MutByGene.cfm). Most pa- ogy screen, were negative. A Lyme antibody titer tients with CMTX, including those with a deletion of was normal. Varicella zoster and Epstein-Barr anti- the GJB1 gene, have a similar degree of neuropathy, body titers were consistent with prior infections. indicating that most mutations probably cause a loss Very long chain fatty acid levels were normal. A of function.1 In agreement, many Cx32 mutants do diagnosis of probable ADEM was made and he was not form functional gap junctions,4 often related to treated with high-dose IV corticosteroids for 3 days. their aberrant trafficking to the cell membrane.5 In A subsequent outpatient evaluation revealed high- addition to their peripheral neuropathy, many pa- arched feet, hyporeflexia at the ankles, and minimal tients have asymptomatic evidence of brain involve- weakness in ankle dorsiflexion. There was a family ment, such as abnormal brainstem auditory evoked history of CMT—in his mother, two maternal uncles, responses (BAER).6,7 Patients have also been found a maternal aunt and her son, the maternal grand- to have abnormal brain MRI results in association mother, and the maternal great-grandmother. None with transient CNS symptoms.8-11 Here, we report a of these family members reported similar transient patient who had two episodes resembling acute de- neurologic episodes. The patient’s mother had nor- myelinating encephalomyelitis (ADEM), the first ep- mal results on brain MRI; the other affected family isode preceding the diagnosis of CMTX. members did not have brain MRI performed. Se- quencing GJB1 (performed by Athena Diagnostics, Case report. A 12-year-old boy presented in Janu- Worchester, MA) from the patient revealedaCtoT ary 1999 with three consecutive episodes of transient mutation at nucleotide position 285, predicted to re- neurologic dysfunction, over the course of 3 days, sult in an amino acid change from arginine to trypto- with complete recovery between each episode. Ini- phan at codon 75 (R75W). Other family members tially, he had numbness of the right face and arm, were presumed to have the same mutation. paresis of the right arm and face, and dysarthria, In November 2002, at age 15, he presented again From the Department of Neurology (Drs. Taylor and Scherer), Hospital of the University of Pennsylvania, Philadelphia; and Departments of Radiology (Dr. Simon) and Pediatric Neurology (Dr. Marks), Children’s Hospital of Philadelphia, PA. Received May 19, 2003. Accepted in final form July 21, 2003. Address correspondence and reprint requests to Dr. Robert Taylor, Department of Neurology, The University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104; e-mail: [email protected] Copyright © 2003 by AAN Enterprises, Inc. 1475 Figure 1. Episode 1: Axial fat-suppressed fluid attenuated inversion recovery (FLAIR) (A) (repetition time/echo time/in- version time 9,000/119/2,200 msec) through the centrum semiovale shows the bilaterally symmetric regions of abnormal T2 hyperintensity. Calculated apparent diffusion coefficient map (ADC) (4,000/100) (B) demonstrates the reduced diffu- sion as hypointensity in the same regions. Axial fat-suppressed FLAIR (C) shows the abnormal hyperintensity in the sple- nium with corresponding reduction in diffusion shown on ADC (D). Episode 2: Axial fat-suppressed FLAIR (E) shows the recurrent T2 signal abnormality in similar regions to episode 1. ADC (F) reveals reduction in diffusion in the affected ar- eas. Eleven-week follow-up: Axial fat-suppressed FLAIR (G) shows mild residual T2 signal abnormality with resolution of the lesions on ADC (H). with 2 days of mild right arm weakness and worsen- tions, including T55I, E102deleted, R142W, and ing handwriting. After wrestling with his brother on R164W, C168Y.8-11 These patients had various combi- the second day, he developed a severe hemiparesis of nations of dysarthria; dysphagia; expressive aphasia; the left face and arm, dysarthria, and dysphagia, mono-, para-, hemi-, and quadriparesis; disorienta- lasting about 8 hours, which then resolved com- tion; ataxia; incoordination; and cranial neuropa- pletely over several hours. MR performed 2 days thies. Episodes began suddenly or progressed over later again showed symmetric abnormally increased days, typically lasting hours to days, sometimes fluc- T2 signal and diffusion reduction in the posterior tuating or recurring multiple times during a period frontal and parietal white matter bilaterally, in ap- of several weeks. Patients seem to recover com- proximately the same distribution as the MR 4 years pletely without any specific therapy. Individual at- earlier (figure 1, E and F), again with no abnormal tacks seem to be provoked by travel to high enhancement. Routine laboratory studies and CSF altitudes, respiratory distress, or fever/infection, but were normal, and oligoclonal bands were absent. He can be unprovoked. The CSF is normal, suggestive was not treated with corticosteroids and had recov- that inflammation is not a primary etiology. There- ered completely without any specific therapy. Repeat fore, high dose corticosteroids may not be beneficial. brain MRI performed 11 weeks later showed a re- The diagnosis of CMTX should be considered in a turn to normal diffusion and improvement in the patient who has a family history of CMT and an abnormal T2 signal with some mild areas of persis- unusual ADEM-like illness, especially with white tently increased T2 signal in the white matter (fig- matter findings on MRI. ure 1, G and H). MRI obtained acutely shows increased T2- weighted signal, sometimes associated with reduc- Discussion. This patient initially presented with tion in diffusion but no abnormal enhancement, an unusual ADEM-like attack, was subsequently predominantly in the posterior centrum semiovale, found to have CMTX, and then presented again with splenium of the corpus callosum, and sometimes the another ADEM-like attack. ADEM-like attacks have middle cerebellar peduncles.8-11 The MRI lesions are been described in individuals with other GJB1 muta- largely confluent in the deep white matter and spare 1476 NEUROLOGY 61 December (1 of 2) 2003 Table Summary of CNS mutants, their phenotypes, and the ers were not reported to have had an MRI.15,16 An- localization of the mutant protein (if known) in transfected cells other patient with CMTX had hypoperfusion of the Mutation Phenotype Localization5,18 cerebellum shown on SPECT (iodine-123-N- isopropyl-p-iodoamphetamine), but reportedly had W24C EPR12 ND normal results on brain MRI.17 Thus, subclinical in- M34V EPR* Golgi & GJP volvement is common, but is not necessarily associ- A39V EPR26 ER ated with abnormal MRI findings. The disruption of gap junction communication be- T55I Abnormal MRI8 ER tween oligodendrocytes and astrocytes may be the D66N EPR† ND cellular mechanism by which GJB1 mutations cause R75W Abnormal MRI Golgi a “CNS phenotype.” Certain Cx32 mutants may have M93V EPR27 Golgi & GJP dominant-negative effects on other connexins ex- pressed in oligodendrocytes—Cx29 and Cx4718-20— E102 deleted Abnormal MRI11 ND thereby decreasing their expression. Astrocytes 12 E109 stop Abnormal MRI ND express different connexins than do oligodendro- R142W Abnormal MRI9 Golgi cytes, so that Cx32 and/or Cx47 would likely interact R164Q Abnormal MRI13 Golgi with Cx26, Cx30, and/or Cx43 on the astrocytic cell 21 R164W Abnormal MRI10 Golgi membrane. Interestingly, dominant mutations of GJA1/Cx43 are also associated with abnormal white C168Y Abnormal MRI9 ND matter signal on MRI.22 The physiologic conse- R183H Abnormal MRI14 Golgi & GJP quences of disrupting the gap junction–mediated T191 frameshift EPR12 ND coupling between oligodendrocytes and astrocytes likely lead to an inability of these cells to regulate * Dr. Steven Scherer, unpublished. † Dr. Richard Sater, personal communication. fluid exchange. This could explain the restricted dif- EPR ϭ extensor plantar responses; ER ϭ endoplasmic reticulum; ND ϭ not determined; GJP ϭ gap junction plaques. the subcortical U fibers. These abnormalities have been reported to persist for months, even after the patient is asymptomatic, and may or may not resolve completely.9,11 Abnormal MRI have also been re- ported in patients with CMTX who were not reported to have had an ADEM-like illness.
Load more

Recommended publications
  • SRC Antibody - N-Terminal Region (ARP32476 P050) Data Sheet
    SRC antibody - N-terminal region (ARP32476_P050) Data Sheet Product Number ARP32476_P050 Product Name SRC antibody - N-terminal region (ARP32476_P050) Size 50ug Gene Symbol SRC Alias Symbols ASV; SRC1; c-SRC; p60-Src Nucleotide Accession# NM_005417 Protein Size (# AA) 536 amino acids Molecular Weight 60kDa Product Format Lyophilized powder NCBI Gene Id 6714 Host Rabbit Clonality Polyclonal Official Gene Full Name V-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) Gene Family SH2D This is a rabbit polyclonal antibody against SRC. It was validated on Western Blot by Aviva Systems Biology. At Aviva Systems Biology we manufacture rabbit polyclonal antibodies on a large scale (200-1000 Description products/month) of high throughput manner. Our antibodies are peptide based and protein family oriented. We usually provide antibodies covering each member of a whole protein family of your interest. We also use our best efforts to provide you antibodies recognize various epitopes of a target protein. For availability of antibody needed for your experiment, please inquire (). Peptide Sequence Synthetic peptide located within the following region: QTPSKPASADGHRGPSAAFAPAAAEPKLFGGFNSSDTVTSPQRAGPLAGG This gene is highly similar to the v-src gene of Rous sarcoma virus. This proto-oncogene may play a role in the Description of Target regulation of embryonic development and cell growth. SRC protein is a tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase. Mutations in this gene could be involved in the
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • New Developments in Charcot–Marie–Tooth Neuropathy and Related Diseases
    CE: Alpana; WCO 300505; Total nos of Pages: 10; WCO 300505 REVIEW CURRENT OPINION New developments in Charcot–Marie–Tooth neuropathy and related diseases Davide Pareyson, Paola Saveri, and Chiara Pisciotta Purpose of review Charcot–Marie–Tooth disease (CMT) and related neuropathies represent a heterogeneous group of hereditary disorders. The present review will discuss the most recent advances in the field. Recent findings Knowledge of CMT epidemiology and frequency of the main associated genes is increasing, with an overall prevalence estimated at 10–28/100 000. In the last years, the huge number of newly uncovered genes, thanks to next-generation sequencing techniques, is challenging the current classification of CMT. During the last 18 months other genes have been associated with CMT, such as PMP2, MORC2, NEFH, MME, and DGAT2. For the most common forms of CMT, numerous promising compounds are under study in cellular and animal models, mainly targeting either the protein degradation pathway or the protein overexpression. Consequently, efforts are devoted to develop responsive outcome measures and biomarkers for this overall slowly progressive disorder, with quantitative muscle MRI resulting the most sensitive-to-change measure. Summary This is a rapidly evolving field where better understanding of pathophysiology is paving the way to develop potentially effective treatments, part of which will soon be tested in patients. Intense research is currently devoted to prepare clinical trials and develop responsive outcome measures. Keywords
    [Show full text]
  • X-Linked Diseases: Susceptible Females
    REVIEW ARTICLE X-linked diseases: susceptible females Barbara R. Migeon, MD 1 The role of X-inactivation is often ignored as a prime cause of sex data include reasons why women are often protected from the differences in disease. Yet, the way males and females express their deleterious variants carried on their X chromosome, and the factors X-linked genes has a major role in the dissimilar phenotypes that that render women susceptible in some instances. underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the Genetics in Medicine (2020) 22:1156–1174; https://doi.org/10.1038/s41436- heart, blood, skin, muscle, and bones. Summarized here are many 020-0779-4 examples of the different presentations in males and females. Other INTRODUCTION SEX DIFFERENCES ARE DUE TO X-INACTIVATION Sex differences in human disease are usually attributed to The sex differences in the effect of X-linked pathologic variants sex specific life experiences, and sex hormones that is due to our method of X chromosome dosage compensation, influence the function of susceptible genes throughout the called X-inactivation;9 humans and most placental mammals – genome.1 5 Such factors do account for some dissimilarities. compensate for the sex difference in number of X chromosomes However, a major cause of sex-determined expression of (that is, XX females versus XY males) by transcribing only one disease has to do with differences in how males and females of the two female X chromosomes. X-inactivation silences all X transcribe their gene-rich human X chromosomes, which is chromosomes but one; therefore, both males and females have a often underappreciated as a cause of sex differences in single active X.10,11 disease.6 Males are the usual ones affected by X-linked For 46 XY males, that X is the only one they have; it always pathogenic variants.6 Females are biologically superior; a comes from their mother, as fathers contribute their Y female usually has no disease, or much less severe disease chromosome.
    [Show full text]
  • SUPPLEMENTARY MATERIAL Effect of Next
    SUPPLEMENTARY MATERIAL Effect of Next-Generation Exome Sequencing Depth for Discovery of Diagnostic Variants KKyung Kim1,2,3†, Moon-Woo Seong4†, Won-Hyong Chung3, Sung Sup Park4, Sangseob Leem1, Won Park5,6, Jihyun Kim1,2, KiYoung Lee1,2*‡, Rae Woong Park1,2* and Namshin Kim5,6** 1Department of Biomedical Informatics, Ajou University School of Medicine, Suwon 443-749, Korea 2Department of Biomedical Science, Graduate School, Ajou University, Suwon 443-749, Korea, 3Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea, 4Department of Laboratory Medicine, Seoul National University Hospital College of Medicine, Seoul 110-799, Korea, 5Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-806, Korea, 6Epigenomics Research Center, Genome Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea http//www. genominfo.org/src/sm/gni-13-31-s001.pdf Supplementary Table 1. List of diagnostic genes Gene Symbol Description Associated diseases ABCB11 ATP-binding cassette, sub-family B (MDR/TAP), member 11 Intrahepatic cholestasis ABCD1 ATP-binding cassette, sub-family D (ALD), member 1 Adrenoleukodystrophy ACVR1 Activin A receptor, type I Fibrodysplasia ossificans progressiva AGL Amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase Glycogen storage disease ALB Albumin Analbuminaemia APC Adenomatous polyposis coli Adenomatous polyposis coli APOE Apolipoprotein E Apolipoprotein E deficiency AR Androgen receptor Androgen insensitivity
    [Show full text]
  • Full Disclosure Forms
    Expanding genotype/phenotype of neuromuscular diseases by comprehensive target capture/NGS Xia Tian, PhD* ABSTRACT * Wen-Chen Liang, MD Objective: To establish and evaluate the effectiveness of a comprehensive next-generation * Yanming Feng, PhD sequencing (NGS) approach to simultaneously analyze all genes known to be responsible for Jing Wang, MD the most clinically and genetically heterogeneous neuromuscular diseases (NMDs) involving spi- Victor Wei Zhang, PhD nal motoneurons, neuromuscular junctions, nerves, and muscles. Chih-Hung Chou, MS Methods: All coding exons and at least 20 bp of flanking intronic sequences of 236 genes causing Hsien-Da Huang, PhD NMDs were enriched by using SeqCap EZ solution-based capture and enrichment method fol- Ching Wan Lam, PhD lowed by massively parallel sequencing on Illumina HiSeq2000. Ya-Yun Hsu, PhD ; 3 Thy-Sheng Lin, MD Results: The target gene capture/deep sequencing provides an average coverage of 1,000 per Wan-Tzu Chen, MS nucleotide. Thirty-five unrelated NMD families (38 patients) with clinical and/or muscle pathologic Lee-Jun Wong, PhD diagnoses but without identified causative genetic defects were analyzed. Deleterious mutations Yuh-Jyh Jong, MD were found in 29 families (83%). Definitive causative mutations were identified in 21 families (60%) and likely diagnoses were established in 8 families (23%). Six families were left without diagnosis due to uncertainty in phenotype/genotype correlation and/or unidentified causative Correspondence to genes. Using this comprehensive panel, we not only identified mutations in expected genes but Dr. Wong: also expanded phenotype/genotype among different subcategories of NMDs. [email protected] or Dr. Jong: Conclusions: Target gene capture/deep sequencing approach can greatly improve the genetic [email protected] diagnosis of NMDs.
    [Show full text]
  • Neurological Diseases Caused by Ion-Channel Mutations Frank Weinreich and Thomas J Jentsch*
    409 Neurological diseases caused by ion-channel mutations Frank Weinreich and Thomas J Jentsch* During the past decade, mutations in several ion-channel humans. This is probably the case for important Na+-chan- genes have been shown to cause inherited neurological nel isoforms, such as those dominating excitation in diseases. This is not surprising given the large number of skeletal muscle or heart, and may also be the case for the different ion channels and their prominent role in signal two channel subunits that assemble to form M-type processing. Biophysical studies of mutant ion channels in vitro K+-channels, which are key regulators of neuronal allow detailed investigations of the basic mechanism excitability [8••,9•]. This concept is supported by the underlying these ‘channelopathies’. A full understanding of observation that many channelopathies are paroxysmal these diseases, however, requires knowing the roles these (i.e. cause transient convulsions): mutations leading to a channels play in their cellular and systemic context. Differences constant disability might be incompatible with life, or may in this context often cause different phenotypes in humans and significantly decrease the frequency of the mutation with- mice. The situation is further complicated by the developmental in the human population. In contrast to the severe effects and other secondary effects that might result from ion- symptoms associated with the loss of function of certain channel mutations. Recent studies have described the different key ion channels, the large number of ion-channel isoforms thresholds to which ion-channel function must be decreased in may lead to a functional redundancy under most circum- order to cause disease.
    [Show full text]
  • Charcot-Marie-Tooth Disease Type 1A and Inflammatory-Demyelinating Lesions in the Central Nervous System
    ISSN: 2378-3001 García-Estévez et al. Int J Neurol Neurother 2019, 6:080 DOI: 10.23937/2378-3001/1410080 International Journal of Volume 6 | Issue 1 Open Access Neurology and Neurotherapy CASE REPORT Charcot-Marie-Tooth Disease Type 1A and Inflammatory- Demyelinating Lesions in the Central Nervous System Daniel A García-Estévez*, Carmen Cid-Rodríguez and Guillermo Ozaita-Arteche Check for Neurology Service, University Hospital of Ourense, Ourense, Spain updates *Corresponding author: Daniel Apolinar García-Estévez, Neurology Service, University Hospital of Ourense, Calle Ramón Puga Noguerol, 52, 32005, Ourense, Spain autosomal dominant, autosomal recessive or X-linked Abstract inheritance pattern [1]. Mutations in the MFN2, GJB1, Charcot-Marie-Tooth disease (CMT) is a hereditary senso- MPZ, NDRG and PMP22 genes have been associated with rimotor polyneuropathy which is occasionally associated with demyelinating lesions in the central nervous system, demyelinating central nervous system (CNS) lesions [2-6]. although it remains unclear whether this finding is coin- Mutations in the 17p11.2 region of the peripheral myelin cidental or whether the two processes share a common protein 22 gene (PMP22) cause CMT1A when the region pathogenic mechanism. is duplicated, and hereditary neuropathy with liability to A male patient with sensorimotor polyneuropathy presented pressure palsy (HNPP) when it is deleted. Both genotypes with symptoms consistent with cauda equina syndrome at are associated with demyelination of the CNS [6,7]. In age 47 in relation to an inflammatory lesion in the conus these cases, the clinical presentation may mimic multiple medullaris. Six years later, he presented with sudden- onset neurological symptoms including dysarthria and right sclerosis (MS) or ischaemic cerebrovascular disease.
    [Show full text]
  • 1 1 2 3 Cell Type-Specific Transcriptomics of Hypothalamic
    1 2 3 4 Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to 5 weight-loss 6 7 Fredrick E. Henry1,†, Ken Sugino1,†, Adam Tozer2, Tiago Branco2, Scott M. Sternson1,* 8 9 1Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 10 20147, USA. 11 2Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, 12 Cambridge CB2 0QH, UK 13 14 †Co-first author 15 *Correspondence to: [email protected] 16 Phone: 571-209-4103 17 18 Authors have no competing interests 19 1 20 Abstract 21 Molecular and cellular processes in neurons are critical for sensing and responding to energy 22 deficit states, such as during weight-loss. AGRP neurons are a key hypothalamic population 23 that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific 24 transcriptomics can be used to identify pathways that counteract weight-loss, and here we 25 report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived 26 young adult mice. For comparison, we also analyzed POMC neurons, an intermingled 27 population that suppresses appetite and body weight. We find that AGRP neurons are 28 considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell 29 type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion 30 channels, neuropeptides, and receptors. Combined with methods to validate and manipulate 31 these pathways, this resource greatly expands molecular insight into neuronal regulation of 32 body weight, and may be useful for devising therapeutic strategies for obesity and eating 33 disorders.
    [Show full text]
  • Aberrant Splicing in GJB1 and the Relevance of 5' UTR in CMTX1
    brain sciences Article Aberrant Splicing in GJB1 and the Relevance of 50 UTR in CMTX1 Pathogenesis Federica Boso 1,2,† , Federica Taioli 1,†, Ilaria Cabrini 1, Tiziana Cavallaro 3 and Gian Maria Fabrizi 1,3,* 1 Department of Neurological Sciences, Biomedicine and Movement Sciences, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy; [email protected] (F.B.); [email protected] (F.T.); [email protected] (I.C.) 2 Department of Cellular, Computational and Integrative Biology, University of Trento, Via Sommarive 9, 38123 Povo (Trento), Italy 3 Azienda Ospedaliera Universitaria Integrata Verona—Borgo Roma, Piazzale L.A. Scuro 10, 37134 Verona, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0458124286 † These Authors contributed equally to the work. Abstract: The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene (GJB1) that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of peripheral nerves. Despite the advances of next-generation sequencing (NGS), attention has only recently also focused on noncoding regions. We describe two unrelated families with a c.-17+1G>T transversion in the 50 untranslated region (UTR) of GJB1 that cosegregates with typical features of CMTX1. As suggested by in silico analysis, the mutation affects the regulatory sequence that controls the proper splicing of the intron in the corresponding mRNA. The retention of the intron is also associated with reduced levels of the transcript and the loss of immunofluorescent staining for Cx32 in the nerve biopsy, thus supporting the hypothesis of mRNA instability as a pathogenic mechanism in these families.
    [Show full text]
  • Genetic Testing Medical Policy – Genetics
    Genetic Testing Medical Policy – Genetics Please complete all appropriate questions fully. Suggested medical record documentation: • Current History & Physical • Progress Notes • Family Genetic History • Genetic Counseling Evaluation *Failure to include suggested medical record documentation may result in delay or possible denial of request. PATIENT INFORMATION Name: Member ID: Group ID: PROCEDURE INFORMATION Genetic Counseling performed: c Yes c No **Please check the requested analyte(s), identify number of units requested, and provide indication/rationale for testing. 81400 Molecular Pathology Level 1 Units _____ c ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (e.g., medium chain acyl dehydrogenase deficiency), K304E variant _____ c ACE (angiotensin converting enzyme) (e.g., hereditary blood pressure regulation), insertion/deletion variant _____ c AGTR1 (angiotensin II receptor, type 1) (e.g., essential hypertension), 1166A>C variant _____ c BCKDHA (branched chain keto acid dehydrogenase E1, alpha polypeptide) (e.g., maple syrup urine disease, type 1A), Y438N variant _____ c CCR5 (chemokine C-C motif receptor 5) (e.g., HIV resistance), 32-bp deletion mutation/794 825del32 deletion _____ c CLRN1 (clarin 1) (e.g., Usher syndrome, type 3), N48K variant _____ c DPYD (dihydropyrimidine dehydrogenase) (e.g., 5-fluorouracil/5-FU and capecitabine drug metabolism), IVS14+1G>A variant _____ c F13B (coagulation factor XIII, B polypeptide) (e.g., hereditary hypercoagulability), V34L variant _____ c F2 (coagulation factor 2) (e.g.,
    [Show full text]
  • Regulation of Cancer Stemness in Breast Ductal Carcinoma in Situ by Vitamin D Compounds
    Author Manuscript Published OnlineFirst on May 28, 2020; DOI: 10.1158/1940-6207.CAPR-19-0566 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Analysis of the Transcriptome: Regulation of Cancer Stemness in Breast Ductal Carcinoma In Situ by Vitamin D Compounds Naing Lin Shan1, Audrey Minden1,5, Philip Furmanski1,5, Min Ji Bak1, Li Cai2,5, Roman Wernyj1, Davit Sargsyan3, David Cheng3, Renyi Wu3, Hsiao-Chen D. Kuo3, Shanyi N. Li3, Mingzhu Fang4, Hubert Maehr1, Ah-Ng Kong3,5, Nanjoo Suh1,5 1Department of Chemical Biology, Ernest Mario School of Pharmacy; 2Department of Biomedical Engineering, School of Engineering; 3Department of Pharmaceutics, Ernest Mario School of Pharmacy; 4Environmental and Occupational Health Sciences Institute and School of Public Health, 5Rutgers Cancer Institute of New Jersey, New Brunswick; Rutgers, The State University of New Jersey, NJ, USA Running title: Regulation of cancer stemness by vitamin D compounds Key words: Breast cancer, cancer stemness, gene expression, DCIS, vitamin D compounds Financial Support: This research was supported by the National Institutes of Health grant R01 AT007036, R01 AT009152, ES005022, Charles and Johanna Busch Memorial Fund at Rutgers University and the New Jersey Health Foundation. Corresponding author: Dr. Nanjoo Suh, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, New Jersey 08854. Tel: 848-445-8030, Fax: 732-445-0687; e-mail: [email protected] Disclosure of Conflict of Interest: “The authors declare no potential conflicts of interest” 1 Downloaded from cancerpreventionresearch.aacrjournals.org on October 1, 2021.
    [Show full text]