Dystrophin expression in the human retina is required for normal function as defined by electroretinography

Pillers, De Ann M.; Bulman, Dennis E.; Weleber, Richard G.; Sigesmund, Dayle A.; Musarella, Maria A.; Powell, Berkley R.; Murphey, William H.; Westall, Carol A.; Panton, Carole M.; Becker, Laurence E.; Worton, Ronald G.; Ray, Peter N.

doi:10.1038/ng0593-82

Cited by 143 publications

(132 citation statements)

References 40 publications

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“…This finding has been amply confirmed (for review, see Blake and Kroger, 2000;Anderson et al, 2002) and extended to include defects in the neural retina (Pillers et al, 1993) (for review, see Schmitz and Drenckhahn, 1997). Likewise, neural defects have been documented in dystrophin-deficient mutant mice, including behavioral and visual abnormalities and alterations in the structure and function of inhibitory cerebellar and retinal photoreceptor synapses Knuesel et al, 1999;Anderson et al, 2003;Green et al, 2004;Vaillend et al, 2004).…”

Section: Introductionmentioning

confidence: 83%

Cerebellar Synaptic Defects and Abnormal Motor Behavior in Mice Lacking α- and β-Dystrobrevin

Grady¹,

Wozniak²,

Ohlemiller³

et al. 2006

J. Neurosci.

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The dystrobrevins (␣DB and ␤DB) bind directly to dystrophin and are components of a transmembrane dystrophin-glycoprotein complex (DGC) that links the cytoskeleton to extracellular proteins in many tissues. We show here that ␣DB, ␤DB, and dystrophin are all concentrated at a discrete subset of inhibitory synapses on the somata and dendrites of cerebellar Purkinje cells. Dystrophin is depleted from these synapses in mice lacking both ␣DB and ␤DB, and DBs are depleted from these synapses in mice lacking dystrophin. In dystrophin mutants and ␣DB,␤DB double mutants, the size and number of GABA receptor clusters are decreased at cerebellar inhibitory synapses, and sensorimotor behaviors that reflect cerebellar function are perturbed. Synaptic and behavioral abnormalities are minimal in mice lacking either ␣DB or ␤DB. Together, our results show that the DGC is required for proper maturation and function of a subset of inhibitory synapses, that DB is a key component of this DGC, and that interference with this DGC leads to behavioral abnormalities. We suggest that motor deficits in muscular dystrophy patients, which are their cardinal symptoms, may reflect not only peripheral derangements but also CNS defects.

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Section: Introductionmentioning

confidence: 83%

Cerebellar Synaptic Defects and Abnormal Motor Behavior in Mice Lacking α- and β-Dystrobrevin

Grady¹,

Wozniak²,

Ohlemiller³

et al. 2006

J. Neurosci.

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“…Accordingly, the expression of the isoforms is directed to specific tissues: Dp427 can be expressed in skeletal and cardiac muscle (Dp427m), brain (Dp427b) and Purkinje cells (Dp427p). Dp260 is almost exclusively expressed in retina, 2 whereas the Dp140 is expressed in brain, retina and kidney 3 and Dp116 only in adult peripheral nerves. 4 Remarkably, the shortest isoform, Dp71, is expressed in most tissues, such as brain, retina, kidney, liver, lung and heart, but not in muscle.…”

Section: Introductionmentioning

confidence: 99%

A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy

Brouwer¹,

Nabuurs

Verhaart

et al. 2013

Eur J Hum Genet

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We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11-Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with b-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P ¼ 0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.

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“…Reduction of the amplitude of the b-wave response is observed in 80% of DMD patients (Cibis et al, 1993;Pillers et al, 1993;Fitzgerald et al, 1994;D'Souza et al, 1995). Reduced amplitude and prolonged implicit time of the b-wave, a response of positive polarity originating primarily from the ON-bipolar cells, have been observed in ERGs from various types of MD model mice Lee et al, 2005;Liu et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Presynaptic Dystroglycan–Pikachurin Complex Regulates the Proper Synaptic Connection between Retinal Photoreceptor and Bipolar Cells

Omori¹,

Araki²,

Chaya³

et al. 2012

J. Neurosci.

104

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Dystroglycan (DG) is a key component of the dystrophin-glycoprotein complex (DGC)at the neuromuscular junction postsynapse. In the mouse retina, the DGC is localized at the presynapse of photoreceptor cells, however, the function of presynaptic DGC is poorly understood. Here, we developed and analyzed retinal photoreceptor-specific DG conditional knock-out (DG CKO) mice. We found that the DG CKO retina showed a reduced amplitude and a prolonged implicit time of the ERG b-wave. Electron microscopic analysis revealed that bipolar dendrite invagination into the photoreceptor terminus is perturbed in the DG CKO retina. In the DG CKO retina, pikachurin, a DG ligand in the retina, is markedly decreased at photoreceptor synapses. Interestingly, in the Pikachurin Ϫ/Ϫ retina, the DG signal at the ribbon synaptic terminus was severely reduced, suggesting that pikachurin is required for the presynaptic accumulation of DG at the photoreceptor synaptic terminus, and conversely DG is required for pikachurin accumulation. Furthermore, we found that overexpression of pikachurin induces formation and clustering of a DG-pikachurin complex on the cell surface. The Laminin G repeats of pikachurin, which are critical for its oligomerization and interaction with DG, were essential for the clustering of the DG-pikachurin complex as well. These results suggest that oligomerization of pikachurin and its interaction with DG causes DG assembly on the synapse surface of the photoreceptor synaptic terminals. Our results reveal that the presynaptic interaction of pikachurin with DG at photoreceptor terminals is essential for both the formation of proper photoreceptor ribbon synaptic structures and normal retinal electrophysiology.

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Dystrophin expression in the human retina is required for normal function as defined by electroretinography

Cited by 143 publications

References 40 publications

Cerebellar Synaptic Defects and Abnormal Motor Behavior in Mice Lacking α- and β-Dystrobrevin

Cerebellar Synaptic Defects and Abnormal Motor Behavior in Mice Lacking α- and β-Dystrobrevin

A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy

Presynaptic Dystroglycan–Pikachurin Complex Regulates the Proper Synaptic Connection between Retinal Photoreceptor and Bipolar Cells

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