| |
|
Kevin M. Flanigan, M.D.
Professor
Nationwide Children's Hospital
Center for Gene Therapy, WA4023
700 Children's Drive
Columbus, OH 43209
Phone: (614)
355-2947
Fax: (614) 722-3273
Email: kevin.flanigan@nationwidechildrens.org
Education & Training:
University of Illinois, Urbana/Champaign, 1986 B.M. in Trumpet
Performance
Rush Medical College, Chicago, Illinois, 1990 M.D.
University of Michigan, Ann Arbor 1990-91 Internship (Internal Medicine)
The Johns Hopkins Hospital, Baltimore 1991-94 Residency (Neurology)
The Johns
Hopkins Hospital, Baltimore 1994-95 Postdoctoral Fellow (Neuromuscular Disease)
University
of Utah, Salt Lake City 1995-97 Postdoctoral Fellow (Neurogentics/Molecular Biology)
Research Interest:
In the laboratory we study mechanisms of pathogenesis in the muscular dystrophies,
and in the clinic setting, we seek to bring novel therapies to patient-based
clinical trials. The most common form of muscular dystrophy are the dystrophinopathies,
which include the more severe Duchenne Muscular Dystrophy (DMD) and the milder
Becker Muscular Dystrophy (BMD). Both DMD and BMD are caused by mutations
in the DMD gene, encoding the dystrophin protein. The major determinant
of severity is whether the mutation results in an mRNA that maintains an open
reading frame that allows translation of a functional amino- and carboxy terminus,
with little impact due to the size of the central rod domain deletion. In
our lab, we study genotype/phenotype correlations with a specific eye toward
exceptions to this reading frame rule, and seek to determine what these mutations
tell us about dystrophin function and DMD disease pathogenesis. As one
example, we have recently defined the first founder disease allele in the DMD gene;
this mutation, along with other nonsense mutations in the 5’ end of the
gene, is associated with very mild BMD, and we have recently defined the alternate
translational initiation sites within DMD exon 6 responsible for phenotypic rescue. Other
mutations identified from patients have led to ongoing projects that seek to
define the function of the dystrophin ZZ domain, and to determine the role of
nonsense-mutation sequence context in rescuing the DMD phenotype by altered mRNA
splicing. The long term goal is to determine potential novel therapeutic
pathways by improving understanding of muscular dystrophy pathogenesis and dystrophin
function.
Selected Publications:
- Flanigan KM, Dunn DM, von Niederhausern A, Soltanzadeh P, Gappmaier
E, Howard MT, Sampson JB, Mendell JR, Wall C, King WM, Pestronk A,
Florence JM, Connolly AM, Mathews KD, Stephan CM, Laubenthal KS, Wong
BL, Morehart PJ, Meyer A, Finkel RS, Bonnemann CG, Medne L, Day JW,
Dalton JC, Margolis MK, Hinton VJ; United Dystrophinopathy Project
Consortium, Weiss RB. (2009) Mutational spectrum of DMD mutations in
dystrophinopathy patients: application of modern diagnostic techniques
to a large cohort. Hum Mutat. Dec;30(12):1657-66.
- Flanigan KM, Dunn DM, von Niederhausern A, Howard MT, Mendell J,
Connolly A, Saunders C, Modrcin A, Dasouki M, Comi GP, Del Bo R, Pickart
A, Jacobson R, Finkel R, Medne L, Weiss RB. (2009 ) DMD Trp3X nonsense
mutation associated with a founder effect in North American families
with mild Becker muscular dystrophy. Neuromuscul Disord. Nov;19(11):743-8.
- Gurvich OL, Maiti B, Weiss RB, Aggarwal G, Howard MT, Flanigan KM.
(2009) DMD exon 1 truncating point mutations: amelioration of phenotype
by alternative translation initiation in exon 6. Hum Mutat.
Apr;30(4):633-40.
- Butterfield RJ, Ramachandran D, Hasstedt SJ, Otterud BE, Leppert
MF, Swoboda KJ, Flanigan KM. (2009) A novel form of juvenile
recessive ALS maps to loci on 6p25 and 21q22. Neuromuscul Disord.
Apr;19(4):279-87.
- Gurvich OL, Tuohy TM, Howard MT, Finkel RS, Medne L, Anderson CB,
Weiss RB, Wilton SD, Flanigan KM. (2008) DMD pseudoexon mutations:
splicing efficiency, phenotype, and potential therapy. Ann Neurol.
Jan;63(1):81-9.
- Lawson VH, Graham BV, Flanigan KM. (2005) Clinical and electrophysiologic
features of CMT2A with mutations in the mitofusin 2 gene. Neurology.
Jul 26;65(2):197-204.
- 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 Genet A. Apr 30;134(3):295-8.
- Howard MT, Anderson CB, Fass U, Khatri S, Gesteland RF, Atkins JF,
Flanigan KM. (2004) Readthrough of dystrophin stop codon mutations
induced by aminoglycosides. Ann Neurol. Mar;55(3):422-6.
- Winokur ST, Chen YW, Masny PS, Martin JH, Ehmsen JT, Tapscott SJ,
van der Maarel SM, Hayashi Y, 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.
- Flanigan KM, von Niederhausern A, Dunn DM, Alder J, Mendell JR, Weiss RB. (2003) Rapid
direct sequence analysis of the dystrophin gene. Am J Hum Genet.
Apr;72(4):931-9.
|
|
