A G+1-&gt;A transversion at the 5' splice site of intron 69 of the dystrophin gene causing the absence of peripheral nerve Dp 116 and severe clinical involvement in a DMD patient

Comi, Giacomo P.; Ciafaloni, Emma; Silva, H.A.Rohan de; Prelle, A.; Bardoni, Alessandra; Rigoletto, C.; Robotti, M.; Bresolin, Nereo; Moggio, Maurizio; Fortunato, Francesco; Ciscato, Patrizia; Turconi, Anna Carla; Rose, Allen D.; Scarlato, G.

doi:10.1093/hmg/4.11.2171

Cited by 25 publications

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“…7C). This localization is consistent with reports that the Dp116 glycoprotein complex is required for maintenance of peripheral myelination (Comi et al, 1995;Saito et al, 2003;Cai et al, 2007).…”

Section: Differences In Onset Of Expression and Localization Of Dp116supporting

confidence: 93%

“…In peripheral nerve, Dp116 and full-length utrophin provide structural support to the outer surface membrane of Schwann cells by linking the actin cytoskeleton and basal lamina (Yamada et al, 1994;Saito et al, 1999;Imamura et al, 2000;Saito et al, 2003). Demyelinating neuropathy has been seen in dystrophic patients with loss of Dp116 (Comi et al, 1995), and myelin instability occurs in animal models in which the dystrophin complex is disrupted (Saito et al, 2003;Cai et al, 2007). Interestingly, the Dp116 complex interacts with the cholesterol transporter that is mutated in Tangier disease, which has a demyelinating peripheral neuropathy phenotype (Züchner et al, 2003;Albrecht et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Cognitive deficits and demyelinating neuropathy have both been seen in dystrophic patients (Comi et al, 1995;Lidov, 1996;Blake and Kroger, 2000;Mehler, 2000). The cognitive impairments lead to speculation that the dystrophin protein family may play a key role at neuronal synapses.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, full-length utrophin is expressed in glia, blood vessels, choroid plexus and pia mater Kamakura et al, 1994;Imamura and Ozawa, 1998;Claudepierre et al, 2000;Knuesel et al, 2000). The dystrophin isoform Dp116 and its associated glycoprotein complex are required for maintenance of peripheral myelination, as seen in animal models of dystrophy and a dystrophic patient with loss of Dp116 (Matsumura et al, 1993;Comi et al, 1995;Saito et al, 1999;Imamura et al, 2000;Masaki et al, 2001;Sherman et al, 2001;Saito et al, 2003;Cai et al, 2007). Cognitive deficits and peripheral neuropathy in dystrophic patients are consistent with both synaptic and glial functions of dystrophin protein family members.…”

Section: Introductionmentioning

confidence: 96%

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Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion

2008

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Muscular dystrophy patients often show cognitive impairment, in addition to muscle degeneration caused by dystrophin gene defects. The cognitive impairments lead to speculation that the dystrophin protein family may play a key role at neuronal synapses. Dystrophin regulates the stability of selected GABA A receptor subtypes and α3-containing nicotinic acetylcholine receptors (nAChRs) at a subset of central GABAergic and peripheral sympathetic nicotinic neuron synapses. Similarly, utrophin, the autosomal homologue of dystrophin, is not required for clustering but indirectly stabilizes muscletype nAChRs at the neuromuscular junction. We examined dystrophin and utrophin expression and localization in the avian parasympathetic ciliary ganglion (CG) to determine whether these proteins play a general role at neuronal nicotinic synapses. We have determined that full-length utrophin and dystrophin and the short dystrophin isoform Dp116 are the major isoforms expressed in the CG based on immunoblotting and immunolabeling. Unexpectedly, the cytoskeletal proteins were not detected at nicotinic synapses or in CG neurons. They are expressed in myelinating and non-myelinating Schwann cells. Further, utrophin expression developmentally precedes that of dystrophin. The proteins show partially overlapping distributions, but also differential accumulation along the surface membrane of Schwann cells adjacent to neuronal somata versus axonal processes. Our findings are consistent with reports that dystrophin protein family members function in the maintenance of cellcell interactions and myelination by anchoring the Schwann cell surface membrane to the basal lamina. In contrast, our results differ from those in skeletal muscle and a subset of sympathetic neurons where utrophin and dystrophin localize at nicotinic synapses.

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Section: Differences In Onset Of Expression and Localization Of Dp116supporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

See 2 more Smart Citations

Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion

2008

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“…First, Dp116 is a Schwann cellspecific isoform of dystrophin, composed mainly of the hinge 4, cysteine-rich, and C-terminal domains containing the ␤-dystroglycan binding site (5,6,29,30). Second, it was reported recently that peripheral myelination was disturbed in a peculiar Duchenne muscular dystrophy patient lacking Dp116 in peripheral nerve because of a unique mutation at the 5Ј splice site of intron 69 of the dystrophin gene (31). In this study, we also investigated the stability of the interaction of the components of the dystroglycan complex in Schwann cells and discussed its implications for the pathogenesis of muscle cell degeneration in sarcoglycanopathy.…”

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confidence: 99%

Characterization of the Transmembrane Molecular Architecture of the Dystroglycan Complex in Schwann Cells

Saito

Masaki

Kamakura

et al. 1999

Journal of Biological Chemistry

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We have demonstrated previously 1) that the dystroglycan complex, but not the sarcoglycan complex, is expressed in peripheral nerve, and 2) that ␣-dystroglycan is an extracellular laminin-2-binding protein anchored to ␤-dystroglycan in the Schwann cell membrane. In the present study, we investigated the transmembrane molecular architecture of the dystroglycan complex in Schwann cells. The cytoplasmic domain of ␤-dystroglycan was co-localized with Dp116, the Schwann cell-specific isoform of dystrophin, in the abaxonal Schwann cell cytoplasm adjacent to the outer membrane. ␤-dystroglycan bound to Dp116 mainly via the 15 C-terminal amino acids of its cytoplasmic domain, but these amino acids were not solely responsible for the interaction of these two proteins. Interestingly, the ␤-dystroglycanprecipitating antibody precipitated only a small fraction of ␣-dystroglycan and did not precipitate laminin and Dp116 from the peripheral nerve extracts. Our results indicate 1) that Dp116 is a component of the submembranous cytoskeletal system that anchors the dystroglycan complex in Schwann cells, and 2) that the dystroglycan complex in Schwann cells is fragile compared with that in striated muscle cells. We propose that this fragility may be attributable to the absence of the sarcoglycan complex in Schwann cells.Dystroglycan is encoded by a single gene and cleaved into two proteins, an extracellular peripheral membrane glycoprotein ␣-dystroglycan and an integral membrane glycoprotein ␤-dystroglycan, by posttranslational processing (1). In skeletal muscle, ␣-dystroglycan links laminin-2 and agrin in the basal lamina with ␤-dystroglycan in the sarcolemma (1-4). On the cytoplasmic side of the sarcolemma, on the other hand, ␤-dystroglycan is anchored to the cytoskeletal protein dystrophin (5, 6). These findings indicate that the dystroglycan complex, comprising ␣-and ␤-dystroglycans, spans the sarcolemma and links the basal lamina with submembranous cytoskeleton, thus contributing to the mechanical stability of the sarcolemma. The recent findings that ␤-dystroglycan interacts with Grb2, an adaptor protein, and rapsyn, a peripheral protein required for acetylcholine receptor clustering, also suggest that the dystroglycan complex may have additional functions in skeletal muscle (7,8).The dystroglycan complex is also expressed in nonmuscle tissues. For instance, the dystroglycan complex, but not the sarcoglycan complex, is expressed in peripheral nerve (9 -11). In peripheral nerve, ␣-and ␤-dystroglycans are expressed restricted to the Schwann cell outer membrane apposing the endoneurial basal lamina but not in the Schwann cell inner membrane or compact myelin, whereas laminin-2 and the nonneuronal isoform of agrin lacking acetylcholine receptor clustering activity are expressed in the endoneurial basal lamina (9 -16). Recently, we have demonstrated that Schwann cell ␣-dystroglycan is a mucin-type glycoprotein, which links laminin-2 and agrin in the endoneurium with ␤-dystroglycan in the Schwann cell outer membrane (11-13). Becaus...

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Are Dp71 and Dp140 brain dystrophin isoforms related to cognitive impairment in Duchenne muscular dystrophy?

Billard²,

et al. 1998

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Molecular study and neuropsychological analysis were performed concurrently on 49 patients with Duchenne muscular dystrophy (DMD) in order to find a molecular explanation for the cognitive impairment observed in most DMD patients. Complete analysis of the dystrophin gene was performed to define the localization of deletions and duplications in relation to the different DMD promoters. Qualitative analysis of the Dp71 transcript and testing for the specific first exon of Dp140 were also carried out. Neuropsychological analysis assessed verbal and visuospatial intelligence, verbal memory, and reading skills. Comparison of molecular and psychometric findings demonstrated that deletions and duplications that were localized in the distal part of the gene seemed to be preferentially associated with cognitive impairment. Two altered Dp71 transcripts and two deleted Dp140 DNA sequences were found in four patients with severe cerebral dysfunction. These findings suggest that some sequences located in the distal part of the gene and, in particular, some DMD isoforms expressed in the brain may be related to the cognitive impairment associated with DMD.

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A G+1->A transversion at the 5' splice site of intron 69 of the dystrophin gene causing the absence of peripheral nerve Dp 116 and severe clinical involvement in a DMD patient

Cited by 25 publications

References 0 publications

Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion

Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion

Characterization of the Transmembrane Molecular Architecture of the Dystroglycan Complex in Schwann Cells

Are Dp71 and Dp140 brain dystrophin isoforms related to cognitive impairment in Duchenne muscular dystrophy?

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