Please use this identifier to cite or link to this item: http://repositorio.unifesp.br/handle/11600/49603
Title: Als5/spg11/kiaa1840 mutations cause autosomal recessive axonal charcot-marie-tooth disease
Authors: Montecchiani, Celeste
Pedace, Lucia
Lo Giudice, Temistocle
Casella, Antonella
Mearini, Marzia
Gaudiello, Fabrizio
Pedroso, Jose Luiz [UNIFESP]
Terracciano, Chiara
Caltagirone, Carlo
Massa, Roberto
St George-Hyslop, Peter H.
Barsottini, Orlando Graziani Povoas [UNIFESP]
Kawarai, Toshitaka
Orlacchio, Antonio
Keywords: Als5/Spg11/Kiaa1840 Mutations
Axonal Degeneration
Charcot-Marie-Tooth Disease
SpatacsinHereditary Spastic Paraplegia
Thin Corpus-Callosum
Motor Neuropathy
Silver-Syndrome
Mfn2 Mutations
Spg11 Gene
Spatacsin
Phenotype
Heterogeneity
Form
Issue Date: 2016
Publisher: Oxford univ press
Citation: Brain. Oxford, v. 139, n. 1, p. 73-85, 2016.
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.
URI: http://repositorio.unifesp.br/handle/11600/49603
ISSN: 0006-8950
Other Identifiers: https://doi.org/10.1093/brain/awv320
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