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- Dominant Intermediate Charcot-Marie-Tooth Type C Maps to Chr...Dominant Intermediate Charcot-Marie-Tooth Type C Maps to Chromosome 1p34-p35
The American Journal of Human Genetics, Volume 73, Issue 6, 1 December 2003, Pages 1423-1430
Albena Jordanova, Florian P. Thomas, Velina Guergueltcheva, Ivailo Tournev, Francisco A.A. Gondim, Borjana Ishpekova, Els De Vriendt, An Jacobs, Ivan Litvinenko, Neviana Ivanova, Borjan Buzhov, Peter De Jonghe, Ivo Kremensky and Vincent Timmerman
AbstractDominant intermediate Charcot-Marie-Tooth (DI-CMT) neuropathy is a genetic and phenotypic variant of classical CMT, characterized by intermediate nerve conduction velocities and histological evidence of both axonal and demyelinating features. We report two unrelated families with intermediate CMT linked to a novel locus on chromosome 1p34-p35 (DI-CMTC). The combined haplotype analysis in both families localized the DI-CMTC gene within a 6.3-cM linkage interval flanked by markers D1S2787 and D1S2830. The functional and positional candidate genes, Syndecan 3 (), and lysosomal-associated multispanning membrane protein 5 () were excluded for pathogenic mutations.
Abstract | Full Text | PDF (327 kb) - Mutations in the Small GTP-ase Late Endosomal Protein RAB7 C...Mutations in the Small GTP-ase Late Endosomal Protein RAB7 Cause Charcot-Marie-Tooth Type 2B Neuropathy
The American Journal of Human Genetics, Volume 72, Issue 3, 1 March 2003, Pages 722-727
Kristien Verhoeven, Peter De Jonghe, Katrien Coen, Nathalie Verpoorten, Michaela Auer-Grumbach, Jennifer M. Kwon, David FitzPatrick, Eric Schmedding, Els De Vriendt, An Jacobs, Veerle Van Gerwen, Klaus Wagner, Hans-Peter Hartung and Vincent Timmerman
AbstractCharcot-Marie-Tooth type 2B (CMT2B) is clinically characterized by marked distal muscle weakness and wasting and a high frequency of foot ulcers, infections, and amputations of the toes because of recurrent infections. CMT2B maps to chromosome 3q13-q22. We refined the CMT2B locus to a 2.5-cM region and report two missense mutations (Leu129Phe and Val162Met) in the small GTP-ase late endosomal protein RAB7 which causes the CMT2B phenotype in three extended families and in three patients with a positive family history. The alignment of RAB7 orthologs shows that both missense mutations target highly conserved amino acid residues. RAB7 is ubiquitously expressed, and we found expression in sensory and motor neurons.
Abstract | Full Text | PDF (1349 kb) - A HOX Gene Mutation in a Family with Isolated Congenital Ver...A HOX Gene Mutation in a Family with Isolated Congenital Vertical Talus and Charcot-Marie-Tooth Disease
The American Journal of Human Genetics, Volume 75, Issue 1, 1 July 2004, Pages 92-96
Antony E. Shrimpton, E. Mark Levinsohn, Justin M. Yozawitz, David S. Packard, Robert B. Cady, Frank A. Middleton, Antonio M. Persico and David R. Hootnick
AbstractCongenital vertical talus (CVT), also known as “rocker-bottom foot” deformity, is a dislocation of the talonavicular joint, with rigid dorsal dislocation of the navicular over the neck of the talus. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance. In contrast, Charcot-Marie-Tooth disease (CMT) is thought to be a completely distinct heterogeneous group of disorders, with foot abnormalities that typically develop a high-arched “claw foot” appearance later in life. In the present study, DNA was isolated from 36 members of a single upstate (northern) New York white family of Italian descent in which both CVT and CMT were segregating. Whole-genome linkage analysis with Affymetrix GeneChip Mapping 10K Array defined a 7-Mb critical region on chromosome 2q31, which led to candidate-gene sequencing of six genes and detection of a single missense mutation, M319K (956T→A), in the gene. In the study family, this mutation was fully penetrant and exhibited significant evidence of linkage (LOD 6.33; θ=), and it very likely accounts for both CVT and CMT in heterozygotes.
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Copyright © 2004 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 74, Issue 6, 1128-1135, 1 June 2004
doi:10.1086/421054
DNA/RNA Helicase Gene Mutations in a Form of Juvenile Amyotrophic Lateral Sclerosis (ALS4)
Ying-Zhang Chen1, Craig L. Bennett1, Huy M. Huynh1, Ian P. Blair1, Imke Puls3, Joy Irobi4, Ines Dierick4, Annette Abel3, Marina L. Kennerson6, 7, Bruce A. Rabin8, Garth A. Nicholson6, 7, Michaela Auer-Grumbach9, Klaus Wagner9, Peter De Jonghe4, 5, John W. Griffin8, Kenneth H. Fischbeck3, Vincent Timmerman4, David R. Cornblath8 and Phillip F. Chance1, 2, 
, 
1 Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington, Seattle
2 Department of Neurology, University of Washington, Seattle
3 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda
4 Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp
5 Department of Neurology, University Hospital of Antwerp, Antwerp
6 Neurobiology Laboratory, ANZAC Research Institute, University of Sydney, Sydney
7 Concord Hospital, Sydney
8 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore
9 Institute of Medical Biology and Human Genetics, Karl Franzens University, Graz, Austria
Address for correspondence and reprints: Dr. Phillip F. Chance, Department of Pediatrics, Box 356320, Room RR247, University of Washington, Seattle, WA 98195.Abstract
Juvenile amyotrophic lateral sclerosis (ALS4) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS) characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span. The ALS4 locus maps to a 1.7-Mb interval on chromosome 9q34 flanked by D9S64 and D9S1198. To identify the molecular basis of ALS4, we tested 19 genes within the ALS4 interval and detected missense mutations (T3I, L389S, and R2136H) in the Senataxin gene (SETX). The SETX gene encodes a novel 302.8-kD protein. Although its function remains unknown, SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing. These observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing.
