Characterization-Novel Subtypes-Inherited Neuropathies
Principal Investigator: Victoria H Lawson
Affiliation: University of Utah
Abstract: The goal of this project is to clinically characterize and define gene mutations responsible for novel and unusual forms of inherited neuropathies (Charcot-Marie-Tooth) in large Utah families. Charcot-Marie-Tooth (CMT) is one of the most common degenerative neurological disorders with a prevalence of 1 in 2500. It is a clinically heterogeneous group of disorders with distal limb muscle weakness, wasting, and sensory loss usually presenting in childhood or early adulthood and typical skeletal abnormalities. The broad classification of CMT into types 1 and 2 based on electrophysiology and pathology is giving way to genetic classification, reflecting significant genetic heterogeneity. At least 10 CMT gene loci have been defined. The applicant proposes to identify and extensively phenotype novel and unusual forms of CMT by studying large kindreds. Linkage analysis will be performed, then a genome wide screen using polymorphic markers across the genome. Candidate genes in the region of linked loci will be identified from the growing Human Genome Project database and mutation analysis will be performed. One large Utah kindred with an axonal form of CMT has already been studied in detail and no linkage to described loci has been found. Therefore, this represents a completely novel form of axonal CMT. A genome-wide screen for linkage is underway. To date 221 screening markers across the genome have been genotyped, and of these, 1 candidate locus has been identified with a LOD score of nearly 2. Four additional large kindreds have been ascertained: Historical data has been collected on many of these family members and clinical/ electrophysiologic examination is underway. The largest kindred has a maximum simulated LOD score of 9.74. Preliminary data suggest these families may be phenotypically distinct from the family already described and, in at least one kindred, from previously described phenotypes. Therefore, these families may represent additional novel loci. Through an NIH funded K30 award, the University of Utah General Clinical Research Center provides a unique didactic program of training in clinical research focused on the inherited basis of human disease. This program incorporates access to resources such as multiuser core facilities, large research centers at the University, and a designated unit in the University Hospital, with specific, mentored, intensive research experiences for maturing clinical investigators. Thus, the University of Utah provides an ideal environment for maximizing the potential of this project and this project applicant. Molecular characterization of novel and unusual forms of CMT will define basic biologic processes of peripheral nerve function, and may lead to new diagnostic and therapeutic approaches.
Funding Period: 2002-01-21 - 2007-12-31
more information: NIH RePORT
- Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 geneVictoria H Lawson
Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84132 2305, USA
Neurology 65:197-204. 2005..The authors report three additional CMT2A families associated with novel mutations in highly conserved regions of the Mfn2 GTPase domain...
- Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutationsElizabeth A Amiott
Department of Biochemistry, University of Utah School of Medicine, 15 N Medical Drive East, Salt Lake City, UT 84112, USA
Exp Neurol 211:115-27. 2008..We discuss our results and those of others in terms of a comprehensive model for the mechanism(s) by which mutations in MFN2 may lead to CMT2A disease...