Kevin Flanigan
Associate Professor of Human Genetics and of Neurology
B.S. University of Illinois
M.D. Rush Medical College
Research
Our laboratory's efforts are directed towards the molecular characterization of inherited neurologic diseases, with a particular emphasis on diseases of peripheral nerve and muscle.
One of the major interests of the lab is to characterize the functional implications of mutations in the DMD gene. DMD, the largest gene known on a genomic scale (2.4 mega bases) encodes for dystrophin. Absence for dystrophin is associated with the severe childhood Duchenne Muscular Dystrophy (DMD) and the milder allelic variant Becker Muscular Dystrophy (BMD). Around 2/3 of DMD and BMD cases are due to deletions in the DMD gene, with the vast majority of BMD cases due to deletions that preserve the reading frame. In collaboration with Dr. Robert Weiss, we have developed a method for rapid and economic direct sequence analysis of the dystrophin gene, allowing the identification of many previously undetectable mutations. Several mutations identified suggest novel functions of the dystrophin protein and efforts are underway to characterize the functional consequences of these mutations. For example, a specific missense mutation dystrophin c. terminus suggests the presence of asiat un-identifying the binding partners of the dystrophin gene.
The second major emphasis of the lab is characterization of the protein gigaxonin, encoded by the gene GAN. Mutations in GAN result in Giant Axonal Neuropathy, a rare childhood disorder characterized by motor and sensory neuropathy with a striking pathologic feature of large accumulations of closely packed neurofilaments within the axon. We are creating two transgenic in a knockout model of Giant Axonal Neuropathy, using a variety of laboratory techniques to identify molecular pathways in which gigaxonin functions.
Ongoing work in the lab also is directed toward mapping traits in large Utah families. We recently have used similar strategies for mapping Spinocerebellar Ataxia, Congenital Muscular Dystrophy, and Charcot-Marie-Tooth associated genes. Several factors make the Utah population ideal for study of dominant traits, and ongoing efforts in the laboratory are directed toward mapping common neurologic disease genes, including ones associated with essential tremor and hereditary spastic paraplegia.
References
1. Lawson VH, Graham BV, Flanigan KM (2005) Clinical and electrophysiologic features of CMT2A with novel mutations in the Mfn2 Gene. Neurology, In Press
2. Mercuri E, Lampe A, Allsopp J, Knight R, Pane M, Kinali M, Bonnemann C, Flanigan K , Bushby K, Pepe G, Muntoni F (2005) Muscle MRI in collagen VI related disorders. Neuromuscul Disord. Apr;15(4):303-10
3. Howard MT, Aggarwal G, Anderson CB, Khatri S, Flanigan KM, Atkins JF (2005) Recoding elements located adjacent to a subset of eukaryal selenocysteine-specifying UGA codons. EMBO J. Mar 24
4. Dent KM, Dunn DM, von Niederhausern AC, Aoyagi AT, Kerr L, Bromberg MB, Hart KJ, Tuohy T, White S, den Dunnen JT, Weiss RB, Flanigan KM (2005) Improved molecular diagnosis of dystrophinopathies in an unselected clinical cohort. Am J Med Genetics Feb134A:295-298
5. Lampe AK, Dunn DM, von Niederhausern AC, Hamil C, Aoyagi A, Laval SH, Maire SK, Chu M-L, Swoboda K, Muntoni F, Bonnemann CG, Flanigan KM, Bushby KMD, Weiss RB (2005) Automated genomic sequence analysis of the three Collagen VI genes: applications to Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy. J Med Genetics Feb ;42:108-120
6. Howard MT, Anderson CB, Fass U, Khatri S, Gesteland RF, Atkins JF, Flanigan KM (2004) Aminoglycosides suppress only a subset of premature stop codon mutations in the dystrophin gene. Ann Neurol Mar;55(3):422-6
7. Winokur ST, Szabo PE, Chen Y-W, van der Maarel S, Tapscott SJ, Martin J, Chung S-A, Ehmsen JT, Flanigan KM (2003) Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation. Hum Mol Genet. Nov 15;12(22):2895-907
8. Flanigan KM, von Niederhausern A, Dunn D, Alder J, Mendell J, Weiss R (2003) Rapid Sequence Analysis of the Dystrophin Gene. American Journal of Human Genetics 72:931-939
9. Brockmann K, Pouwels PJW, Dechent P, Flanigan KM, Frahm J, Hanefeld F (2003) Cerebral proton magnetic resonance spectroscopy of a patient with giant axonal neuropathy. Brain Dev . Jan;25(1):45-50
10. Flanigan KM, Coffeen C, Sexton L, Brunner SL, Stauffer D, Leppert M (2001) Genetic Characterization of a Large, Historically Significant Utah Family with Facioscapulohumeral Dystrophy. Neuromuscular Disorders 11:525-529
11. Howard MT, Shirts BH, Petros LM, Flanigan KM, Gesteland RF, Atkins JF (2000) Sequence Specificity of Aminoglycoside Induced Stop Codon Readthrough: Potential Implications for Treatment of Duchenne Muscular Dystrophy. Annals of Neurology 48:164-169
12. Coffeen CM, McKenna CE, Koeppen AH, Plaster NM, Maragakis N, Mihalopoulos J, Schwankhaus JD, Flanigan KM, Gregg R, Ptacek LJ, Fu YH (2000) Genetic Localization of an Autosomal Dominant Leukodystrophy Mimicking Chronic Progressive Multiple Sclerosis to Chromosome 5q31. Human Molecular Genetics 9(5):787-793
