Als5/spg11/kiaa1840 mutations cause autosomal recessive axonal charcot-marie-tooth disease

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dc.contributor.author Montecchiani, Celeste
dc.contributor.author Pedace, Lucia
dc.contributor.author Lo Giudice, Temistocle
dc.contributor.author Casella, Antonella
dc.contributor.author Mearini, Marzia
dc.contributor.author Gaudiello, Fabrizio
dc.contributor.author Pedroso, Jose Luiz [UNIFESP]
dc.contributor.author Terracciano, Chiara
dc.contributor.author Caltagirone, Carlo
dc.contributor.author Massa, Roberto
dc.contributor.author St George-Hyslop, Peter H.
dc.contributor.author Barsottini, Orlando Graziani Povoas [UNIFESP]
dc.contributor.author Kawarai, Toshitaka
dc.contributor.author Orlacchio, Antonio
dc.date.accessioned 2019-01-21T10:30:08Z
dc.date.available 2019-01-21T10:30:08Z
dc.date.issued 2016
dc.identifier https://doi.org/10.1093/brain/awv320
dc.identifier.citation Brain. Oxford, v. 139, n. 1, p. 73-85, 2016.
dc.identifier.issn 0006-8950
dc.identifier.uri http://repositorio.unifesp.br/handle/11600/49603
dc.description.abstract Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for similar to 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease. en
dc.description.sponsorship Italian Ministero della Salute [GR09.109]
dc.description.sponsorship Comitato Telethon Fondazione Onlus, Italy [GGP10121]
dc.description.sponsorship Universita di Roma "Tor Vergata", Rome, Italy [E82I15000190005]
dc.description.sponsorship Rotary Club Sanluri Medio Campidano, Sanluri (VS), Italy (Grant Noi per Voi)
dc.description.sponsorship Japan Society for the Promotion of Science (JSPS KAKENHI) [26461294]
dc.description.sponsorship Ministry of Health, Labour, and Welfare of Japan
dc.description.sponsorship Brain Science Foundation, Japan
dc.format.extent 73-85
dc.language.iso eng
dc.publisher Oxford univ press
dc.relation.ispartof Brain
dc.rights Acesso aberto
dc.subject Als5/Spg11/Kiaa1840 Mutations en
dc.subject Axonal Degeneration en
dc.subject Charcot-Marie-Tooth Disease en
dc.subject SpatacsinHereditary Spastic Paraplegia en
dc.subject Thin Corpus-Callosum en
dc.subject Motor Neuropathy en
dc.subject Silver-Syndrome en
dc.subject Mfn2 Mutations en
dc.subject Spg11 Gene en
dc.subject Spatacsin en
dc.subject Phenotype en
dc.subject Heterogeneity en
dc.subject Form en
dc.title Als5/spg11/kiaa1840 mutations cause autosomal recessive axonal charcot-marie-tooth disease en
dc.type Artigo
dc.description.affiliation Laboratorio di Neurogenetica, CERC - IRCCS Santa Lucia, Rome, Italy
dc.description.affiliation Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy
dc.description.affiliation Department of Neurology, Universidade Federal de São Paulo, Brazil
dc.description.affiliation Laboratorio di Neurologia Clinica e Comportamentale, IRCCS Santa Lucia, Rome, Italy
dc.description.affiliation Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
dc.description.affiliation Department of Medicine, University of Toronto, Toronto, Ontario, Canada
dc.description.affiliation Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
dc.description.affiliation Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
dc.description.affiliationUnifesp Department of Neurology, Universidade Federal de São Paulo, Brazil
dc.description.sponsorshipID Italian Ministero della Salute: GR09.109
dc.description.sponsorshipID Comitato Telethon Fondazione Onlus, Italy: GGP10121
dc.description.sponsorshipID Universita di Roma "Tor Vergata", Rome, Italy: E82I15000190005
dc.description.sponsorshipID JSPS KAKENHI: 26461294
dc.identifier.doi 10.1093/brain/awv320
dc.description.source Web of Science
dc.identifier.wos WOS:000370205000020



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