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ID 115028
Title Alternative
KIAA1840 mutations cause ARCMT2
Author
Montecchiani, Celeste IRCCS Santa Lucia
Pedace, Lucia IRCCS Santa Lucia
Giudice, Temistocle Lo IRCCS Santa Lucia|Universita` di Roma “Tor Vergata”
Casella, Antonella IRCCS Santa Lucia
Mearini, Marzia IRCCS Santa Lucia
Gaudiello, Fabrizio IRCCS Santa Lucia
Pedroso, José L. Universidade Federal de Sa˜o Paulo
Terracciano, Chiara Universita` di Roma “Tor Vergata”
Caltagirone, Carlo Universita` di Roma “Tor Vergata”|IRCCS Santa Lucia
Massa, Roberto Universita` di Roma “Tor Vergata”
St George-Hyslop, Peter H. University of Toronto|University of Cambridge
Barsottini, Orlando G. P. Universidade Federal de Sa˜o Paulo
Orlacchio, Antonio IRCCS Santa Lucia|Universita` di Roma “Tor Vergata”
Keywords
ALS5/SPG11/KIAA1840 mutations
axonal degeneration
Charcot–Marie–Tooth disease
spatacsin
Content Type
Journal Article
Description
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 ∼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.
Journal Title
Brain
ISSN
00068950
14602156
NCID
AA00573228
AA12095112
Publisher
Oxford University Press
Volume
139
Issue
1
Start Page
73
End Page
85
Published Date
2015-11-10
Rights
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
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language
eng
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departments
Medical Sciences