Effects of dystrophin isoforms on signal transduction through neural retina

Genotype-phenotype analysis of Duchenne muscular dystrophy mouse mutants

De Ann M Pillers, Richard Weleber, Daniel G. Green, Sean M. Rash, Ghassan Y. Dally, Perry L. Howard, Michael (Mike) Powers, Donald C. Hood, Verne M. Chapman, Peter N. Ray, William Woodward

Research output: Contribution to journalArticle

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Abstract

Duchenne and Becker muscular dystrophy patients have mutations in the dystrophin gene. Most show reduced b-wave amplitudes in the dark-adapted electroretinogram (ERG). We studied normal C57BL/6J mice and five X-linked muscular dystrophy strains with different dystrophin mutations to determine whether the location of the mutation within the gene affects the mouse ERG and to correlate such effects with dystrophin isoform expression. Amplitudes and implicit times were measured for a-waves, b-waves, and digitally filtered oscillatory potentials, mdx and mdx(Cv5) mice, with mutations near the amino terminus and lacking expression of Dp427, had ERGs similar to those of C57BL/6J mice. mdx(Cv2) and mdx(Cv4) mice, with mutations in the center of dystrophin and who do not express isoforms Dp427, Dp260, or Dp140 (mdx(Cv4)), had increased b-wave and oscillatory potential implicit times, mdx(Cv3) mice, with a mutation near the carboxy terminus resulting in deficiency of all dystrophin isoforms, had increased b-wave and oscillatory potential implicit times and reduced scotopic b-wave amplitudes. Fitting the a-wave data to a transduction activation phase mathematical model showed normal responses for all phenotypes, suggesting that the b-wave delays are due to defects beyond the rod outer segment, most likely at the rod to on-bipolar cell synapse. The variation in the ERG phenotype with the position of the dystrophin gene mutation suggests that there are different contributions by each isoform to retinal electrophysiology. Although Dp427 and Dp140 isoforms do not appear to be important contributors to the ERG, lack of Dp260 and possibly Dp71 isoforms is associated with an abnormal ERG.

Original languageEnglish (US)
Pages (from-to)100-110
Number of pages11
JournalMolecular Genetics and Metabolism
Volume66
Issue number2
DOIs
StatePublished - Feb 1999

Fingerprint

Signal transduction
Dystrophin
Duchenne Muscular Dystrophy
Retina
Signal Transduction
Protein Isoforms
Genotype
Phenotype
Mutation
Inbred mdx Mouse
Genes
Inbred C57BL Mouse
Rod Cell Outer Segment
Gene Order
Electrophysiology
Muscular Dystrophies
Synapses
Theoretical Models
Chemical activation
Mathematical models

Keywords

  • Animal model
  • B-wave
  • Duchenne muscular dystrophy
  • Dystrophin
  • Electroretinogram
  • Genotype-phenotype correlation

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Endocrinology, Diabetes and Metabolism

Cite this

Effects of dystrophin isoforms on signal transduction through neural retina : Genotype-phenotype analysis of Duchenne muscular dystrophy mouse mutants. / Pillers, De Ann M; Weleber, Richard; Green, Daniel G.; Rash, Sean M.; Dally, Ghassan Y.; Howard, Perry L.; Powers, Michael (Mike); Hood, Donald C.; Chapman, Verne M.; Ray, Peter N.; Woodward, William.

In: Molecular Genetics and Metabolism, Vol. 66, No. 2, 02.1999, p. 100-110.

Research output: Contribution to journalArticle

Pillers, De Ann M ; Weleber, Richard ; Green, Daniel G. ; Rash, Sean M. ; Dally, Ghassan Y. ; Howard, Perry L. ; Powers, Michael (Mike) ; Hood, Donald C. ; Chapman, Verne M. ; Ray, Peter N. ; Woodward, William. / Effects of dystrophin isoforms on signal transduction through neural retina : Genotype-phenotype analysis of Duchenne muscular dystrophy mouse mutants. In: Molecular Genetics and Metabolism. 1999 ; Vol. 66, No. 2. pp. 100-110.
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