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 G.; Green, Daniel G.; Rash, Sean M.; Dally, Ghassan Y.; Howard, Perry L.; Powers, Michael R.; Hood, Donald C.; Chapman, Verne M.; Ray, Peter N.; Woodward, William R.

doi:10.1006/mgme.1998.2784

Cited by 55 publications

(81 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Panel a shows typical ERGs evoked by a moderately intense flash (log I = −1.5). As previously reported for the ERG of intact and anesthetized mdx Cv3 mice (Pillers et al, ,1999b, the ERG from the isolated retina is predominantly negative. The b-wave amplitudes in panel b were measured from the trough of the a-wave to the peak of the b-wave.…”

Section: Reduced and Delayed B-wavesupporting

confidence: 82%

“…It takes 20 ms longer for the mdx Cv3 responses to rise out of the noise of recording and yet the rising edge of the response to the same intensity is not markedly different in shape. Since the photoreceptor delay in mdx Cv3 is not different from wild type (Pillers et al, 1999b and Fig. 2), we conclude that there is an increase in the synaptic delay at the rod-to-rod bipolar synapse.…”

Section: Discussionmentioning

confidence: 64%

“…2 provides evidence that the rod photocurrents in the mdx Cv3 are the same as those of the normal mice. An earlier study in the intact mouse in which the leading edge of the a-wave was analyzed suggested that this might be the case (Pillers et al, 1999b). The responses in Fig.…”

Section: Discussionmentioning

confidence: 80%

“…As is the case in man, the ERG changes in mouse models correlate with mutations that affect dystrophin isoform Dp260 (Pillers et al, 1999b). The mdx Cv3 mouse also has reduced expression of α-and β-dystroglycan (Dalloz et al, 2001).…”

mentioning

confidence: 87%

See 3 more Smart Citations

Normal photoresponses and alteredb-wave responses to APB in themdx^Cv3mouse isolated retina ERG supports role for dystrophin in synaptic transmission

2004

Self Cite

View full text Add to dashboard Cite

The mdx Cv3 mouse is a model for Duchenne muscular dystrophy (DMD). DMD is an X-linked disorder with defective expression of the protein dystrophin, and which is associated with a reduced b-wave and has other electroretinogram (ERG) abnormalities. To assess potential causes for the abnormalities, we recorded ERGs from pieces of isolated C57BL/6J and mdx Cv3 mouse retinas, including measurements of transretinal and intraretinal potentials. The ERGs from the isolated mdx Cv3 retina differ from those of control retinas in that they show reduced b-wave amplitudes and increased b-wave implicit times. Photovoltages obtained by recording across the photoreceptor outer segments of the retinas did not differ from normal, suggesting that the likely causes of the reduced b-wave are localized to the photoreceptor to ON-bipolar synapse. At a concentration of 50 μM, the glutamate analog DL-2-amino-4-phosphonobutyric acid (APB) blocks the b-wave component of the ERG, by binding to sites on the postsynaptic membrane. The On-bipolar cell contribution to the ERG was inferred by extracting the component that was blocked by APB. We found that this component was smaller in amplitude and had longer response latencies in the mdx Cv3 mice, but was of similar overall time course. To assess the sensitivity of sites on the postsynaptic membrane to glutamate, the concentration of APB in the media was systematically varied, and the magnitude of blockage of the light response was quantified. We found that the mdx Cv3 retina was 5-fold more sensitive to APB than control retinas. The ability of lower concentrations of APB to block the b-wave in mdx Cv3 suggests that the ERG abnormalities may reflect alterations in either glutamate release, the glutamate postsynaptic binding sites, or in other proteins that modulate glutamate function in ON-bipolar cells.

show abstract

Section: Reduced and Delayed B-wavesupporting

confidence: 82%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 87%

See 2 more Smart Citations

Normal photoresponses and alteredb-wave responses to APB in themdx^Cv3mouse isolated retina ERG supports role for dystrophin in synaptic transmission

2004

Self Cite

View full text Add to dashboard Cite

show abstract

“…7 Dystrophin has also been assigned a signalling role; although some of these activities are relevant for skeletal muscle function (eg, modulation of adrenergic tone by nNOS), 8 others are essential for dystrophin function in organs such as the brain and retina. 9,10 Furthermore, different dystrophin isoforms are localised in distinct regions of the central nervous system (CNS) and the retina. Absence of dystrophin from these sites is responsible for the extraneuromuscular manifestations of DMD including neurodevelopmental disorders 11 and disturbances in retinal electrophysiology.…”

Section: Introductionmentioning

confidence: 99%

Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system

Ricotti

Jägle²,

Theodorou

et al. 2015

Eur J Hum Genet

View full text Add to dashboard Cite

Multiple isoforms of dystrophin (Dp427, Dp260, Dp140, Dp71) are expressed differentially in the central nervous system (CNS) including the retinal layers. Disruption of these protein products is responsible for cognitive dysfunction, electroretinogram (ERG) abnormalities and behavioural disorders in Duchenne muscular dystrophy (DMD). We studied the ocular characteristics and neuropsychiatric profile of 16 DMD boys. The ISCEV standard, full-field flash ERGs were assessed. Intellectual ability and behavioural disturbances were measured. All genotypes were associated with mildly abnormal photopic ERG a:b-wave amplitude ratios. In addition, we identified the following genotype/phenotype correlations: boys with mutations upstream of exon 30 (ie, isolated Dp427 altered expression) showed normal scotopic a:b ratios, abnormal photopic oscillatory potential OP2 and normal scotopic OP2. Conversely, all boys with DMD mutations downstream of exon 30 showed profoundly 'negative' scotopic ERGs (a:b ratios 41). In these patients, the involvement of Dp260 isoform resulted in the absence of slow rod pathway signalling in15 Hz scotopic flicker ERGs. These boys had abnormal scotopic OP2 and normal photopic OP2. Finally, children with mutations also affecting Dp71 were associated with more pronounced electronegative ERGs. When correlating ERGs to neurodevelopmental outcome, we found a positive correlation between negative scotopic ERGs and neurodevelopmental disturbances, and the most severe findings were in boys with Dp71 disruption. These findings suggest a strong association between DMD mutations affecting different DMD isoforms with characteristically abnormal scotopic ERGs and severe neurodevelopmental problems. The role of the ERG as a potential biomarker for dystrophin function in the CNS and response to novel genetic therapies warrants further exploration.

show abstract

Retinal Function in Carriers of Bardet-Biedl Syndrome

Cox

Hansen²,

Quinn³

et al. 2003

Arch Ophthalmol

View full text Add to dashboard Cite

To test the hypothesis that carriers of Bardet-Biedl syndrome have abnormal rod-mediated responses. Methods: Parents (n = 26) of children with Bardet-Biedl syndrome (BBS), who are obligate carriers of BBS, consented to scotopic, full-field electroretinography (ERG). Responses were recorded over a 4 to 5 log unit range, up to a maximum stimulus of approximately +3.6 log scotopic troland seconds. The parameters of activation of the rod photoresponse, S (sensitivity parameter) and R mp3 (amplitude of the saturated rod response), were derived by fitting a transduction model to the ERG awaves. For the b-wave, the stimulus producing a half maximum response (log) and the saturated amplitude (V max) were determined. The model of the rod photoresponse was subtracted from the intact ERG to demonstrate a corneal positive potential (P 2) , and log k P2 and P 2max were determined. The carriers' ERG responses were compared with those of healthy control subjects (n=26). Main Outcome Measures: Sensitivity (S, log , and log k P2) and saturated amplitude (R mp3 , V max , and P 2max) of receptoral and postreceptoral response components. Results: All parents had decreased P 2 sensitivity, and most (15 [60%] of 26) had decreased b-wave sensitivity. The rod photoresponse sensitivity and the saturated amplitudes of the rod cell response, b-wave and P 2 , did not differ significantly between carriers and controls. Conclusions: Diminished P 2 sensitivity is characteristic of the carriers of BBS. The site of the primary defect in the BBS rod pathway appears to be proximal to the outer segments, most likely before the rod-bipolar cell synapse.

show abstract

Effects of Dystrophin Isoforms on Signal Transduction through Neural Retina: Genotype–Phenotype Analysis of Duchenne Muscular Dystrophy Mouse Mutants

Cited by 55 publications

References 48 publications

Normal photoresponses and alteredb-wave responses to APB in themdx^Cv3mouse isolated retina ERG supports role for dystrophin in synaptic transmission

Normal photoresponses and alteredb-wave responses to APB in themdx^Cv3mouse isolated retina ERG supports role for dystrophin in synaptic transmission

Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system

Retinal Function in Carriers of Bardet-Biedl Syndrome

Contact Info

Product

Resources

About

Effects of Dystrophin Isoforms on Signal Transduction through Neural Retina: Genotype–Phenotype Analysis of Duchenne Muscular Dystrophy Mouse Mutants

Cited by 55 publications

References 48 publications

Normal photoresponses and alteredb-wave responses to APB in themdxCv3mouse isolated retina ERG supports role for dystrophin in synaptic transmission

Normal photoresponses and alteredb-wave responses to APB in themdxCv3mouse isolated retina ERG supports role for dystrophin in synaptic transmission

Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system

Retinal Function in Carriers of Bardet-Biedl Syndrome

Contact Info

Product

Resources

About

Normal photoresponses and alteredb-wave responses to APB in themdx^Cv3mouse isolated retina ERG supports role for dystrophin in synaptic transmission

Normal photoresponses and alteredb-wave responses to APB in themdx^Cv3mouse isolated retina ERG supports role for dystrophin in synaptic transmission