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SH3TC2/KIAA1985 Protein Is Required for Proper Myelination and the Integrity of the Node of Ranvier in the Peripheral Nervous System

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SH3TC2/KIAA1985 Protein Is Required for Proper Myelination and the Integrity of the Node of Ranvier in the Peripheral Nervous System Corrections CHEMISTRY NEUROSCIENCE Correction for “Depression of reactivity by the collision energy Correction for “SH3TC2/KIAA1985 protein is required for in the single barrier H + CD4 → HD + CD3 reaction,” by proper myelination and the integrity of the node of Ranvier in Weiqing Zhang, Yong Zhou, Guorong Wu, Yunpeng Lu, Huilin the peripheral nervous system,” by Estelle Arnaud, Jennifer Pan, Bina Fu, Quan Shuai, Lan Liu, Shu Liu, Liling Zhang, Zenker, Anne-Sophie de Preux Charles, Claudia Stendel, Bo Jiang, Dongxu Dai, Soo-Ying Lee, Zeng Xie, Bastiaan J. Andreas Roos, Jean-Jacques Médard, Nicolas Tricaud, Joachim Braams, Joel M. Bowman, Michael A. Collins, Dong H. Zhang, Weis, Ueli Suter, Jan Senderek, and Roman Chrast, which ap- and Xueming Yang, which appeared in issue 29, July 20, 2010, of peared in issue 41, October 13, 2009, of Proc Natl Acad Sci USA Proc Natl Acad Sci USA (107:12782–12785; first published July 6, (106:17528–17533; first published September 29, 2009; 10.1073/ 2010; 10.1073/pnas.1006910107). pnas.0905523106). The authors note that author name Zeng Xie should have The authors note that Henning Kleine and Bernhard Luscher appeared as Zhen Xie. The online version has been corrected. should be added to the author list between Nicolas Tricaud and The corrected author line appears below. Joachim Weis. Henning Kleine should be credited with performing Weiqing Zhanga,1, Yong Zhoua,1, Guorong Wua, Yunpeng research. Bernhard Luscher should be credited with analyzing Lub,HuilinPana, Bina Fua,QuanShuaia,LanLiua,ShuLiua, data. The online version has been corrected. The corrected author Liling Zhangb,BoJianga,DongxuDaia, Soo-Ying Leeb,Zhen and affiliation lines, and author contributions appear below. Xiec,BastiaanJ.Braamsd,JoelM.Bowmane, Michael A. Collinsf,DongH.Zhanga,2, and Xueming Yanga,2 Estelle Arnauda, Jennifer Zenkera,b, Anne-Sophie de Preux Charlesa, Claudia Stendelc, Andreas Roosd, Jean-Jacques www.pnas.org/cgi/doi/10.1073/pnas.1011320107 Médarda,NicolasTricaudc, Henning Kleinee,Bernhard Luschere, Joachim Weisf,UeliSuterc, Jan Senderekc,d,f,and Roman Chrasta,1 MICROBIOLOGY Correction for “Clostridium ljungdahlii represents a microbial pro- aDepartment of Medical Genetics and bGraduate Program in Neurosciences, duction platform based on syngas,” by Michael Köpke, Claudia Held, University of Lausanne, CH-1005 Lausanne, Switzerland; cInstitute of Cell Biology, Eidgenössische Technische Hochschule (ETH) Zurich, CH-8093 Zurich, Sandra Hujer, Heiko Liesegang, Arnim Wiezer, Antje Wollherr, Switzerland; Institutes of dHuman Genetics and fNeuropathology, Rheinisch- Armin Ehrenreich, Wolfgang Liebl, Gerhard Gottschalk, and Peter Westfälische Technische Hochschule (RWTH) Aachen University, 52074 Dürre, which appeared in issue 29, July 20, 2010, of Proc Natl Acad Aachen, Germany; and eInstitute of Biochemistry and Molecular Biology, Sci USA (107:13087–13092; first published July 2, 2010; 10.1073/ Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, pnas.1004716107). 52057 Aachen, Germany The authors note that, due to a printer’s error, the sequence deposition number was not published with the manuscript. The Author contributions: E.A., J.S., and R.C. designed research; E.A., J.Z., A.-S.d.P.C., C.S., A.R., data have been deposited in the GenBank database (accession J.-J.M., H.K., N.T., and R.C. performed research; E.A., J.Z., A.-S.d.P.C., C.S., A.R., B.L., J.W., no. CP001666). U.S., J.S., and R.C. analyzed data; and E.A., N.T., J.W., U.S., J.S., and R.C. wrote the paper. www.pnas.org/cgi/doi/10.1073/pnas.1010816107 www.pnas.org/cgi/doi/10.1073/pnas.1010446107 PROFILE Correction for “Profile of Ronald Levy,” by Beth Azar, which appeared in issue 29, July 20, 2010, of Proc Natl Acad Sci USA (107:12745–12746; first published July 12, 2010; 10.1073/pnas. 1008810107). The editors note that Philip Downey should have been listed as the author of the Profile. This information has been updated online. www.pnas.org/cgi/doi/10.1073/pnas.1011244107 CORRECTIONS www.pnas.org PNAS | August 24, 2010 | vol. 107 | no. 34 | 15305 Downloaded by guest on September 30, 2021 SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system Estelle Arnauda, Jennifer Zenkera,b, Anne-Sophie de Preux Charlesa, Claudia Stendelc, Andreas Roosd, Jean-Jacques Me´ darda, Nicolas Tricaudc, Joachim Weise, Ueli Suterc, Jan Senderekc,d,e, and Roman Chrasta,1 aDepartment of Medical Genetics and bGraduate Program in Neurosciences, University of Lausanne, CH-1005 Lausanne, Switzerland; cInstitute of Cell Biology, Eidgeno¨ ssische Technische Hochschule (ETH) Zurich, CH-8093 Zurich, Switzerland; and Institutes of dHuman Genetics and eNeuropathology, Rheinisch-Westfa¨ lische Technische Hochschule (RWTH), Aachen University of Technology, 52074 Aachen, Germany Edited by Eric M. Shooter, Stanford University School of Medicine, Stanford, CA, and approved July 29, 2009 (received for review May 26, 2009) Charcot–Marie–Tooth disease type 4C (CMT4C) is an early-onset, severity and the age of onset vary in and between families, but autosomal recessive form of demyelinating neuropathy. The clin- usually the sensorimotor neuropathy can be detected in the first ical manifestations include progressive scoliosis, delayed age of decade of life (4–6). In addition to the peripheral neuropathy, walking, muscular atrophy, distal weakness, and reduced nerve almost all patients affected by CMT4C develop early-onset conduction velocity. The gene mutated in CMT4C disease, SH3TC2/ severe scoliosis. KIAA1985, was recently identified; however, the function of the CMT4C has originally been mapped in two large Algerian protein it encodes remains unknown. We have generated knockout families to a 13-cM linkage interval on chromosome 5q23-q33 mice where the first exon of the Sh3tc2 gene is replaced with an (7). By homozygosity mapping and allele-sharing analysis, this enhanced GFP cassette. The Sh3tc2⌬Ex1/⌬Ex1 knockout animals de- interval was narrowed down to a 1.7-megabase region, leading to velop progressive peripheral neuropathy manifested by decreased the identification of mutations in a thus far uncharacterized motor and sensory nerve conduction velocity and hypomyelina- transcript called KIAA1985,orSH3TC2 (4). SH3TC2 encodes a tion. We show that Sh3tc2 is specifically expressed in Schwann cells protein of 1,288 aa containing two Src homology 3 (SH3) and 10 and localizes to the plasma membrane and to the perinuclear tetratricopeptide repeat (TPR) domains sharing no overall NEUROSCIENCE endocytic recycling compartment, concordant with its possible significant similarity to any other human protein with known function in myelination and/or in regions of axoglial interactions. function. The presence of SH3 and TPR domains suggests that Concomitantly, transcriptional profiling performed on the endo- SH3TC2 could act as a scaffold protein. SH3TC2 is well con- neurial compartment of peripheral nerves isolated from control served among vertebrate species, whereas no nonvertebrate and Sh3tc2⌬Ex1/⌬Ex1 animals uncovered changes in transcripts en- orthologs were identified (4). coding genes involved in myelination and cell adhesion. Finally, The role of SH3TC2 in the peripheral nervous system remains detailed analyses of the structures composed of compact and largely unknown. Thus, we decided to analyze its function in vivo ⌬ ⌬ noncompact myelin in the peripheral nerve of Sh3tc2⌬Ex1/⌬Ex1 by creating a Sh3tc2 Ex1/ Ex1 mouse, a model of CMT4C disease. ⌬ ⌬ animals revealed abnormal organization of the node of Ranvier, a By detailed characterization of Sh3tc2 Ex1/ Ex1 peripheral nerve phenotype that we confirmed in CMT4C patient nerve biopsies. development and function, we found that these mice mimic The generated Sh3tc2 knockout mice thus present a reliable model neuropathy phenotypes present in CMT4C patients. Moreover, ⌬ ⌬ of CMT4C neuropathy that was instrumental in establishing a role the characterization of the Sh3tc2 Ex1/ Ex1 mice led to the finding for Sh3tc2 in myelination and in the integrity of the node of of lengthened nodes of Ranvier in these mice. This nodal Ranvier, a morphological phenotype that can be used as an phenotype was confirmed in biopsies from CMT4C patients, additional CMT4C diagnostic marker. providing an additional clinical marker that may improve the diagnostic approach to this disease. Charcot–Marie–Tooth disease ͉ peripheral neuropathy ͉ Schwann cell Results ith an estimated prevalence of 1 in 2,500 persons, Charcot– Mice with a Disrupted Sh3tc2 Gene Develop a Peripheral Neuropathy. Based on described mutations in exon 1 of SH3TC2 in neuropathic Marie–Tooth (CMT) neuropathies [also called hereditary W patients affected by CMT4C leading to a premature stop codon (4), motor and sensory neuropathies (HMSNs)] are among the most we decided to develop a mouse knockout model of CMT4C by common inherited neurological disorders (1). Over the last 25 years, replacing exon 1 of the Sh3tc2 gene with an enhanced GFP progress in genetics has led to the identification of more than 30 (eGFP)-Neo cassette (Fig. 1A). Mice homozygous for the targeted genes responsible for different CMT forms (www.molgen.ua.ac.be/ ⌬ ⌬ allele (Sh3tc2neo Ex1/neo Ex1) were crossed with the deleter strain CMTMutations). Identification of these genes, which encode pro- nestin-Cre to eliminate the neo gene, leading to the generation of teins involved in various glial and axonal functions, contributed ⌬ ⌬ ϩ a Sh3tc2 Ex1 allele. The mating of Sh3tc2 Ex1/ mice led to a normal tremendously both to basic understanding of peripheral nerve Mendelian ratio of the offspring genotypes. The generated Sh3tc2 function and to genetic counseling in affected families. ⌬ ⌬ mutant mice (Sh3tc2 Ex1/ Ex1) lacked exon 1 and expressed eGFP CMT4C is a demyelinating, autosomal recessive CMT neu- instead of Sh3tc2 mRNA (Fig. S1 A–C). We took advantage of the ropathy. The clinical manifestations observed in CMT4C pa- tients include delayed age of walking, muscular atrophy, areflexia, sensory impairment, foot deformities (pes cavus), and Author contributions: E.A., J.S., and R.C.
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