Abstract

Charcot-Marie-Tooth Polyneuropathy Syndrome (CMT) is the most common inherited neuropathy in humans. CMT type 1 is characterized clinically by slowly progressive distal muscle atrophy and weakness, electrophysiologically by decreased motor nerve conduction velocities, neuropathologically by a demyelinating hypertrophic neuropathy and """"""""onion bulb"""""""" formation, and genetically by autosomal dominant segregation of the disease phenotype with most families demonstrating linkage to proximal 17p markers (CMT1A). CMT1A was recently demonstrated to be linked and associated with a large DNA duplication in 17p11.2p12. An animal model for CMT is the Trembler mouse (Tr dominant, TrJ semidominant) which presents similar clinical, electrophysiological, and neuropathological features. The Tr phenotype maps to mouse chromosome 11 in a region syntenic to the proximal region of human 17p; further, a peripheral nerve-specific gene (PMP-22) maps to the appropriate region of mouse chromosome 11 and is mutated in Tr. Preliminary experimental results suggest that the human homologue of the PMP-22 gene maps within the CMT1A duplication. The objective of this proposal is to obtain a complete molecular characterization of the CMT1A duplication region. This includes determining the size of the duplication and identifying the junction of the duplication through physical mapping of the CMT1A region; identifying expressed sequences within the duplication through the construction and screening of cDNA libraries from various human tissues; and determining the frequency of the duplication in CMT patients by means of Southern, pulsed field gel, and polymorphic (GT)n repeat analyses. Investigation of alternative mechanisms for CMT will include mutational analysis of the human PMP-22 gene in non-duplication CMT patients and molecular DNA analysis in partial trisomy 17p patients. The proposed work will lead to a DNA based diagnostic test for the duplication form of CMT and may lead to fundamental understanding of the molecular genetics and neurobiology of some inherited neuropathies. This understanding may elucidate options for therapeutic intervention for some forms of CMT.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS027042-04
Application #
3413196
Study Section
Neurology C Study Section (NEUC)
Project Start
1990-01-01
Project End
1996-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Lupski, James R; Belmont, John W; Boerwinkle, Eric et al. (2011) Clan genomics and the complex architecture of human disease. Cell 147:32-43
Inoue, Ken; Ohyama, Tomoko; Sakuragi, Yosuke et al. (2007) Translation of SOX10 3'untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain. Hum Mol Genet 16:3037-46
Khajavi, Mehrdad; Shiga, Kensuke; Wiszniewski, Wojciech et al. (2007) Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse: a potential therapy for inherited neuropathy. Am J Hum Genet 81:438-53
Khajavi, Mehrdad; Inoue, Ken; Lupski, James R (2006) Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur J Hum Genet 14:1074-81
Lee, Jennifer A; Inoue, Ken; Cheung, Sau W et al. (2006) Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease. Hum Mol Genet 15:2250-65
Szigeti, Kinga; Nelis, Eva; Lupski, James R (2006) Molecular diagnostics of Charcot-Marie-Tooth disease and related peripheral neuropathies. Neuromolecular Med 8:243-54
Lee, Jennifer A; Madrid, Ricardo E; Sperle, Karen et al. (2006) Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann Neurol 59:398-403
Shy, Michael E; Scavina, Mena T; Clark, Alisa et al. (2006) T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy. Ann Neurol 59:358-64
Lee, Jennifer A; Cheung, Sau W; Ward, Patricia A et al. (2005) Prenatal diagnosis of PLP1 copy number by array comparative genomic hybridization. Prenat Diagn 25:1188-91
Kurotaki, Naohiro; Shen, Joseph J; Touyama, Mayumi et al. (2005) Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet Med 7:479-83

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