Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort.
Mutations in the DMD gene, encoding the dystrophin protein, are responsible for the dystrophinopathies Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X-linked Dilated Cardiomyopathy (XLDC). Mutation analysis has traditionally been challenging, due to the large gene size (79 exons over 2.2 Mb of genomic DNA). We report a very large aggregate data set comprised of DMD mutations detected in samples from patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy. We report 1,111 mutations in the DMD gene, including 891 mutations with associated phenotypes. These results encompass 506 point mutations (including 294 nonsense mutations) and significantly expand the number of mutations associated with the dystrophinopathies, highlighting the utility of modern diagnostic techniques. Our data supports the uniform hypermutability of CGA>TGA mutations, establishes the frequency of polymorphic muscle (Dp427m) protein isoforms and reveals unique genomic haplotypes associated with "private" mutations. We note that 60% of these patients would be predicted to benefit from skipping of a single DMD exon using antisense oligonucleotide therapy, and 62% would be predicted to benefit from an inclusive multiexonskipping approach directed toward exons 45 through 55.
Flanigan
Kevin M
KM
Departments of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA. kevin.flanigan@genetics.utah.edu
Dunn
Diane M
DM
von Niederhausern
Andrew
A
Soltanzadeh
Payam
P
Gappmaier
Eduard
E
Howard
Michael T
MT
Sampson
Jacinda B
JB
Mendell
Jerry R
JR
Wall
Cheryl
C
King
Wendy M
WM
Pestronk
Alan
A
Florence
Julaine M
JM
Connolly
Anne M
AM
Mathews
Katherine D
KD
Stephan
Carrie M
CM
Laubenthal
Karla S
KS
Wong
Brenda L
BL
Morehart
Paula J
PJ
Meyer
Amy
A
Finkel
Richard S
RS
Bonnemann
Carsten G
CG
Medne
Livija
L
Day
John W
JW
Dalton
Joline C
JC
Margolis
Marcia K
MK
Hinton
Veronica J
VJ
Weiss
Robert B
RB
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D015331:Cohort Studies; D019937:Diagnostic Techniques and Procedures; D016189:Dystrophin / Q000737:chemistry / Q000235:genetics*; D005091:Exons / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D020388:Muscular Dystrophy, Duchenne / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D016189:Dystrophin