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- W2151985655 abstract "As many neuromuscular disorders involve brain as well as muscle, the European Neuromuscular Centre (ENMC) consortium on cognitive impairment in neuromuscular disorders held its first meeting in Naarden (The Netherlands) on the 13–15 July 2001. It was attended by 15 participants from the United Kingdom, France and Italy. In his introductory remarks, Prof. N. Bresolin (Milan, Italy) convenor and chairman of the Consortium, outlined the objectives of the workshop: to gather a panel of experts (clinical, geneticists and basic scientists), to review the available scientific information and find a common strategy of clinical analysis, establishing the criteria of selection of the patients and to define the objectives of shared research projects. Over the last 10 years several approaches concerning possible correlation between molecular defects in genes mainly responsible for muscular diseases and cognitive impairment or between neuroradiological analysis and mental retardation have been published. In order to identify the particular features of neurofunctional, cognitive, psychiatric and visual deficit in neuromuscular disorders, different groups reported their experience on a wide spectrum of patients. Possible correlations between gene/protein alterations and cognitive impairment were discussed in Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy, limb-girdle muscular dystrophies, congenital myopathies and mitochondrial myopathies. The first session was concentrated on the molecular basis of cognitive impairment in DMD and BMD and on the neuropsychological profile of Duchenne patients. Duchenne himself had already noted a ‘caractere obtus’ in many of the children affected by the neuromuscular disease. More specific work in identifying the characters of this intellectual phenotype was done by Karagan and colleagues [[1]Karagan N.J. Intellectual functioning in Duchenne muscular dystrophy: a review.Psychol Bull. 1978; 86: 250-259Crossref Scopus (62) Google Scholar] in 1980: they found a basic language deficit. Leibowitz and Dubowitz [[2]Leibowitz D. Dubowitz V. Intellect and behavior in Duchenne muscular dystrophy.Dev Med Child Neurol. 1981; 23: 577-590Crossref PubMed Scopus (105) Google Scholar] found significant impairment in word-reading ability. The presence of mental retardation and its possible correlation with dystrophin gene alterations in DMD patients has been well recognized since 1992 [[3]Emery A.E.H. Duchenne muscular dystrophy.2nd. 1993; : 115-120Google Scholar], about one third of DMD patients show reduction of intelligence quotient (IQ) associated with specific deficit in verbal rather than performance IQ. The cognitive impairment is not progressive and not correlated with the severity of muscle disease; no clear association has been found between DNA mutations and IQ scores [[4]Comi G.P. Bresolin N. Bardoni A. Absence of mental retardation in a large DMD gene deletion involving brain dystrophin promoter.Neurology. 1993; 43 (Letter): 313Google Scholar]. The muscle disease is caused by the absence of dystrophin, a 427 kDa protein associated with the sarcolemma in skeletal and smooth muscle; since two alternative 427 kDa isoforms are also expressed in the cerebral neocortex and in the cerebellum, it has been hypothesized that they might be important for normal neuronal function or development. Previous studies revealed that intellectual impairment is more frequent in patients carrying deletions in the distal part of the gene (including exons 45–54). The discovery of two carboxy-terminal dystrophin proteins (Dp), Dp71 and Dp140, both expressed in the brain, in addition to the full-length central nervous system dystrophins, may be regarded as an explanation for these findings. Transcription of Dp71 is initiated between exons 62 and 63 [[5]Blake D.J. Love D.R. Tinsley J. et al.Characterization of a 4.8 kb transcript from the Duchenne muscular dystrophy locus expressed in Schwannoma cells.Hum Mol Genet. 1992; 1: 103-109Crossref PubMed Scopus (116) Google Scholar] while Dp140 promoter and first exon are located upstream to exon 45 [[6]Lidov H.G. Selig S. Kunkel L.M. Dp140: a novel 140 kDa CNS transcript from the dystrophin locus.Hum Mol Genet. 1995 Mar; 4: 329-333Crossref PubMed Scopus (231) Google Scholar]. Dr Sironi (Bosisio, Italy) presented the result of genetic analysis concerning patients affected by DMD and BMD clinically followed at the E. Medea Institute and at the University of Milano, over the last 5 years. A first neuropsychological evaluation and genetic analysis of the Dp140 transcription unit was performed on 12 Duchenne and 28 Becker muscular dystrophy patients carrying deletions of variable length either with a 3′-end breakpoint in exon 44 or with a 5′-end breakpoint in exon 45. Comparison of neuropsychological and molecular data showed a statistically significant relationship between loss of Dp140 first exon and mental retardation in BMD (P=0.008). Such a correlation was not evident in Duchenne muscular dystrophy patients but only showed a trend toward significance (P=0.063). It is noteworthy that no patient with normal intelligence showed a deletion involving the Dp140 regulatory region. In order to better clarify the contribution of Dp140 to mental retardation in DMD, a further 44 patients carrying deletions distributed along the gene were analyzed: as expected, there was a significant difference between the IQ scores of patients with proximal versus distal deletions and this latter group of patients displayed median FIQ, PIQ and VIQ values below 77. The same 44 patients were then divided according to the loss or preservation of Dp140 regulatory sequences: two patients with a deletion of Dp140 promoter and first exon and all patients with deletion spanning downstream to exon 51 were supposed to lack Dp140 function. Comparison of FIQ, VIQ and PIQ scores from this group versus the remaining patients showed higher significance than the previous association: 19 patients with normal Dp140 expression had a mean FIQ score of 96, while the 25 patients with altered Dp140 expression had a mean FIQ of 73. In the sample, patients with deletions involving Dp140 gene region presented a median FIQ score lower than the one recorded in the whole group of patients with distal deletion indicating that lesions involving Dp140 gene region might be considered functionally distinct from general distal deletions. Nonetheless, the study was including some exceptions. A patient with a proximal deletion (exons 17–19) displayed one of the lowest IQ scores in the mental retardation group and two subjects presented apparently identical deletions (exons 45–54) but significantly different FIQ scores (93 versus 61). In the sample, one of two untestable patients showed a splice-site mutation in intron 69. This patient, already tested for the absence of the Dp116 isoform, presumably also had an alteration in both Dp71 and Dp140 expression [7Bardoni A. Sironi M. Felisari G. Comi G.P. Bresolin N. Absence of brain Dp140 isoform and cognitive impairment in Becker muscular dystrophy.Lancet. 1999; 353: 897-898Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 8Felisari G. Martinelli Boneschi F. Bardoni A. et al.Loss of Dp140 dystrophin and intellectual impairment in Duchenne dystropphy.Neurology. 2000; 55: 559-564Crossref PubMed Scopus (107) Google Scholar]. This supports the hypothesis that mutations in the Dp71 gene region cause severe cerebral dysfunction, disrupting expression of all brain transcripts as suggested by Moizard et al. [9Moizard M.P. Billard C. Toutain A. Berret F. Marmin N. Moraine C. Are Dp71 and Dp140 brain dystrophin isoforms related to cognitive impairment in Duchenne muscular dystrophy?.Am J Med Genet. 1998; 80: 32-41Crossref PubMed Scopus (100) Google Scholar, 10Moizard M.P. Toutain A. Fournier D. et al.Severe cognitive impairment in DMD: obvious clinical indication for Dp71 isoform point mutation screening.Eur J Hum Genet. 2000; 8: 552-556Crossref PubMed Scopus (94) Google Scholar]. Connecting this point, Dr A. Toutain (Tours Cedex-France) showed her group's results focused on Dp71 point mutation screening. As several investigations have shown that rearrangements in the second part of the dystrophin gene tend to be more commonly associated with cognitive impairment, and several reports have described point mutations in the Dp71 coding region in DMD retarded patients, her group screened for point mutations in the Dp71 coding sequence in DMD patients without detectable deletion or duplication in the whole dystrophin cDNA sequence. Point mutations were found in seven of the 14 patients tested. All mutations were found in patients with cognitive impairment, particularly among the most severely retarded, and not in patients with normal cognitive abilities. In a more recent investigation, they found two promoter-deleted Dp140 transcripts (total absence of Dp71 transcript for one patient and a nonsense mutation for the other one) respectively in four patients with severe cerebral dysfunction. Both patients with Dp140 deletion had a VIQ <70 and bad or no reading acquisition, whereas both patients with altered Dp71 transcripts were psychologically untestable because of severe mental retardation. Taken together, these findings suggest that cognitive impairment in some DMD is related to dysfunction of certain brain dystrophin isoforms and that cognitive impairment is more severe when the mutation is more distal. To support this hypothesis, a group of 12 DMD patients without detectable deletion or duplication in the whole dystrophin cDNA sequence, was screened for point mutation in the Dp71 coding sequence. Four nonsense mutations and one splice (splice-site o splicing mutation) mutation were detected in five severely neuropsychologically impaired children. The identification of the mutation is critical for: (1) genotype-phenotype correlation studies; (2) genetic counselling (carrier detection and prenatal diagnosis) in some families; and (3) possible therapeutic prospects. Point mutation screening remains difficult due to the large size of the dystrophin gene and the great variety of molecular defects: on the other hand, Dp71 is expressed in blood cells and point mutation screening in the Dp71 region is therefore much easier, being feasible by reverse transcriptase-polymerase chain reaction on lymphoblastoid cell lines. Dr Stefania Lilli (San Vito al Tagliamento-Pn-Italy) described a systematic investigation of language functions in seven patients with dystrophinopathy (six DMD, one intermediate phenotype DMD/BMD) who presented a lower verbal IQ than the performance IQ. Analysis of the error percentage in language assessment of each patient shows that morphology is the most impaired linguistic level with the highest percentage of errors, followed by syntax and semantics. At the morphological level the patients showed difficulties in ‘derivational morphology’ and ‘morphological opposites’; they mainly made inflectional errors: agreement in gender and number, verb conjugation. They made omissions, additions or substitutions of free grammar and bound morphemes. At the semantic level difficulties in ‘lexical decision’ were as common as verbal and phonemic paraphasias. Some patients show also word-retrieval difficulties, which are shown by pauses within the utterance, clearly related to difficulties in lexical access. Analysis of spontaneous speech revealed that the greater difficulty was sentence construction (propositioning). Word order (very rare in Italian) and omission of parts of speech such as subjects and verbs were the most frequent morphosyntactic errors. In conclusion, all patients except one showed a discrepancy between PIQ and VIQ and language difficulties. Some of the patients showed difficulties related to morphology, others to syntax and still others to lexical access. These linguistic deficits in DMD sample may suggest that the genetic defect responsible for severe dystrophinopathies is also responsible for specific alterations of particular corticocerebral and cerebellar structures that subserve the organization of language function. Our patients’ relevant difficulties with sentence construction, morphosyntax, lexical access and syntactic comprehension may be explained in terms of altered planning and organization skills which are associated with an altered functioning of the left frontal and left temporoparietal structures. All these data bring to the conclusion that the presence of language disorders in some subjects with dystrophinopathy is associated with a probable neurofunctional alteration of the left hemisphere and some cerebellar structures [[11]Fabbro F. Neurolinguistica e Neuropsicologia dei disturbi specifici del linguaggio nel bambino.Saggi di Neuropsicologia infantile, Psicopedagogia, Riabilitazione. 1999; 24: 11-23Google Scholar]. Professor Bushby (Newcastle, United Kingdom) presented data from Newcastle upon Tyne on the relationship between the position of the deletion in the dystrophin gene and IQ. As with other studies, a relationship between the presence of distal deletions and overall lower IQ was noted, with no 5′ deletions being found in DMD patients with IQ <70 [[12]Bushby K.M. Apleton R. Anderson L.V. Welch J.L. Kelly P. Gardner-Medwin D. Deletion status and intellectual impairment in Duchenne muscular dystrophy.Dev Med Child Neurol. 1995; 37: 260-269Crossref PubMed Scopus (77) Google Scholar]. Several important questions remain however. The first relates to the discrepancy in the IQ score between boys with apparently the same deletion. This could be very variable indeed. The second relates to whether the boys with proximal deletions and normal IQ still had the typical verbal-performance deficit reported across the whole group. If this were present in this group despite the presence of a normal IQ, then it might indicate that there are a number of different mechanisms contributing to the cognitive involvement observed in dystrophinopathies. Limited data were also presented for patients with BMD, which suggested that, overall, this group tended to underachieve relative to their peers. This is in keeping with a general observation that the BMD group often runs into problems with behavior especially in the teenage years which may present a challenge for management. This contrasts with the observation for other similarly disabled groups where different behavioral phenotypes may be observed. The need for further structured research in this area was highlighted to confirm or refute these observations and potentially allow some conclusions about how to help in the management of these complications. Dr J. Chelly (Paris-France) reported his studies on X-linked mental retardation. X-linked mental retardation include a variety of different disorders, vastly heterogeneous, in which affected patients do not have any distinctive clinical or biochemical features in common apart from cognitive impairment. So far, seven X-chromosomal genes responsible for non-specific mental retardation have been identified: FMR2, GDI1, RPS6KA3, IL1RAPL, TM4SF2, OPNH1 and Pak3. The products of some genes have been implicated in neuronal plasticity by controlling the activity of small GTPase of the Rho family; others are involved with cell migration, axon guidance, dendritic outgrowth. Molecular analysis of a reciprocal X/21 translocation in a male with mental retardation showed that the ARHGEF6 (a new MRX gene, also known as αPIX or Cool 2, encoding a protein with homology to guanine nucleotide exchange factors for Rho GTPases) was disrupted by the rearrangement. Mutation screening of 119 patients with non-specific mental retardation revealed a mutation in the first intron of the gene in all affected males of a large family. Dr J. Chelly gave as well the compelling evidence that the methyl-CpG-binding protein 2 (MECP2) gene is involved in X linked mental retardation. He reported mutations in two families that co-segregate with non-specific magnetic resonance (MR) phenotypes which affect only males. In view of these data, they screened MECP2 in a cohort of 185 patients found negative for the expansions across the FRAXA (Fragile X locus A) CGG repeat and reported the identification of mutations in four sporadic cases of MR. All these data suggest that more systematic screenings of some genes in MR patients result in significant progress in the field of molecular diagnosis and genetic counseling of mental handicap. The second part of the workshop was devoted to animal model studies and to new molecules possibly interacting with dystrophin at the neuronal and glial level.Dr Vaillend (Orsay Cedex-France) described the cognitive abilities of two dystrophic mutant mice considered to be models of DMD: the mdx mouse which is deficient in full-length dystrophin in both muscle and brain, and the mdx3Cv mouse lacking all the dystrophin-gene products including the C-terminal short products normally expressed in the brain (Dp71, Dp140).Because the two mutant strains do not display overt motor impairments at the age of testing, they are suitable models to study the role of dystrophins in cognitive and behavioral processes in the absence of muscular weakness. Moreover, the comparison of mouse strains lacking distinct dystrophin-gene products and a precise analysis of the genotype-phenotype correlation is an important strategy for understanding the mechanisms underlying the cognitive impairment in DMD. Behavioral studies in mdx mice led to the conclusion that a deficiency in full-length dystrophin induces specific and moderate learning and memory deficits, characterized by slower procedural learning and impaired long-term consolidation in non-spatial learning tasks [13Vaillend C. Rendon A. Misslin R. Ungerer A. Influence of dystrophin-gene mutation on mdx mouse behavior. I. Retention deficits at long delays in spontaneous alternation and bar-pressing tasks.Behav Genet. 1995; 25: 569-579Crossref PubMed Scopus (92) Google Scholar, 14Vaillend C. Billard J.-M. Dutar P. Claudepierre T. Rendon A. Ungerer A. Spatial discrimination learning and CA1 hippocampal synaptic plasticity in mdx and mdx3cv mice lacking dystrophin-brain isoforms.Neuroscience. 1998; 86: 53-66Crossref PubMed Scopus (32) Google Scholar]. Using electrophysiological methods in hippocampal slices, Dr Vaillend and colleagues also investigated several calcium-dependent forms of synaptic plasticity involved in the basic mechanisms of memory processes (e.g. long-term potentiation or LTP) [[15]Bliss T.V.P. Collingridge G.L. A synaptic model of memory: long-term potentiation in the hippocampus.Nature. 1993; 361: 31-39Crossref PubMed Scopus (9562) Google Scholar]. They found that dystrophin deficiency in mdx mice enhances NMDA receptor (NMDAr)-mediated short-term potentiation of excitatory neurotransmission, without affecting the 1st h of LTP expression [[16]Vaillend C. Ungerer A. Billard J.-M. Facilitated NMDA receptor-mediated synaptic plasticity in the hippocampal CA1 area of dystrophin-deficient mice.Synapse. 1999; 33: 59-70Crossref PubMed Scopus (32) Google Scholar]. This effect was prevented by NMDAr or GABAAr antagonists. Although the specificity of such alterations remains to be further investigated, this is in keeping with the role of dystrophin in the clustering of GABAAr at the neuronal membrane [[17]Knuesel I. Mastrocola M. Zuellig R.A. Bornhauser B. Schaub M.C. Fritschy J.-M. Altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice).Eur J Neurosci. 1999; 11: 4457-4462Crossref PubMed Scopus (191) Google Scholar] and with the possible interaction between dystrophin and proteins associated with the NMDAr [[18]Brenman J.E. Bredt D.S. Synaptic signaling by nitric oxide.Curr Opin Neurobiol. 1997; 7: 374-378Crossref PubMed Scopus (290) Google Scholar]. A suggestive explanation of the memory impairment in mdx mice is given by a role for neuronal dystrophin in NMDAr and/or GABAAr function, which might modulate neuronal excitability and network activity. However, the moderate learning impairments in mdx mice cannot entirely reflect the profound deficits observed in some DMD patients. Can stronger cognitive deficits be expected in mdx3Cv mice lacking Dp71 and Dp140? Although a mild impairment in procedural learning may be a common alteration in the mdx and mdx3Cv mutants, the latter showed weaker learning impairments and no overt electrophysiological alteration [14Vaillend C. Billard J.-M. Dutar P. Claudepierre T. Rendon A. Ungerer A. Spatial discrimination learning and CA1 hippocampal synaptic plasticity in mdx and mdx3cv mice lacking dystrophin-brain isoforms.Neuroscience. 1998; 86: 53-66Crossref PubMed Scopus (32) Google Scholar, 15Bliss T.V.P. Collingridge G.L. A synaptic model of memory: long-term potentiation in the hippocampus.Nature. 1993; 361: 31-39Crossref PubMed Scopus (9562) Google Scholar, 16Vaillend C. Ungerer A. Billard J.-M. Facilitated NMDA receptor-mediated synaptic plasticity in the hippocampal CA1 area of dystrophin-deficient mice.Synapse. 1999; 33: 59-70Crossref PubMed Scopus (32) Google Scholar, 17Knuesel I. Mastrocola M. Zuellig R.A. Bornhauser B. Schaub M.C. Fritschy J.-M. Altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice).Eur J Neurosci. 1999; 11: 4457-4462Crossref PubMed Scopus (191) Google Scholar, 18Brenman J.E. Bredt D.S. Synaptic signaling by nitric oxide.Curr Opin Neurobiol. 1997; 7: 374-378Crossref PubMed Scopus (290) Google Scholar, 19Vaillend C. Ungerer A. Behavioral characterization of mdx3cv mice deficient in C-terminal dystrophins.Neuromuscul Disord. 1999; 9: 296-304Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. These results do not support the hypothesis of a crucial role for Dp71 and Dp140 in the occurrence of a cognitive impairment in DMD, although they may well be explained by the development of compensatory mechanisms in mdx3Cv mice [[20]Vaillend C. Billard J.M. Dutar P. Claudepierre T. Rendon A. Ungerer A. Spatial discrimination learning and CA1 hippocampal synaptic plasticity in mdx and mdx3cv mice lacking dystrophin-brain isoforms.Neuroscience. 1998; 86: 53-66Crossref PubMed Scopus (51) Google Scholar]. Interestingly, mdx3Cv mice, unlike the mdx mice, showed enhanced anxiety-related behaviors as compared to controls. The possible correlation between such behavioral features and mutations affecting Dp71 and/or Dp140 might be an unsuspected feature of the DMD syndrome, which might explain, at least in part, the variable severity of the cognitive deficits. This work in mouse models of DMD indicates that deficiency in full-length dystrophin alone may be responsible for specific learning and memory deficits independent of motor disturbances. The role of Dp71 and Dp140 in the genesis of the cognitive deficits associated with DMD remains to be demonstrated in mice lacking these proteins, and would benefit from the study of new genetic models displaying mutations which might prevent compensatory mechanisms by dystrophin homologues. Dr Derek Blake (Oxford, United Kingdom) presented data on the molecular identification of dystrophin-associated proteins in the brain. The dystrophin-related proteins, alpha- and beta-dystrobrevin are differentially distributed in the brain; alpha-dystrobrevin is localized to glia whereas beta-dystrobrevin is neuronal. Consistent with this idea beta-dystrobrevin forms a complex with dystrophin and is enriched at postsynaptic densities. Using the yeast two-hybrid system, a number of beta-dystrobrevin binding proteins have been identified and are currently being characterized. Dysbindin is a novel coiled-coil containing protein that binds to beta-dystrobrevin in brain and also to alpha-dystrobrevin in muscle. In the brain, dysbindin is found associated with axon terminals and also in some neuronal cell bodies. Whilst little is known about the functional significance of the beta-dystrobrevin: dysbindin interaction; dysbindin is localized to the short arm of chromosome 6 to a region containing an important quantitative trait locus for developmental dyslexia. Dr Blake also showed that, under certain conditions in vitro, beta-dystrobrevin could be preferentially targeted to mitochondria. This targeting is mediated by the interaction between beta-dystrobrevin and a protein that is part of the mitochondrial membrane system called mitofilin. Dr Blake proposed the idea that some of the cognitive defects seen in patients with DMD could be, in part, due to mitochondrial dysfunction in dystrophin or Dp71-deficient neurons. Dr Blake also showed that Dp71 is found in both neurons and glia and could therefore explain why mutations in the Dp71 region of the DMD gene are very frequently associated with severe mental retardation [21Blake D.J. Hawkes D.J. Benson M.A. Beesley P.W. Different dystrophin-like complexes are expressed in neurons and glia.J Cell Biol. 1999; 147: 645-658Crossref PubMed Scopus (156) Google Scholar, 22Culligan K. Glover L. Dowling P. Ohlendiek K. Brain dystrophin-glycoprotein complex: persistent expression of β-dystroglycan, impaired oligomerization of Dp71 and up-regulation of utrophins in animal models of muscular dystrophy.BMC Cell Biol. 2001; 2: 1471-2121Crossref Scopus (47) Google Scholar]. It is now recognized that dystrophins, dystrophin-related proteins (DRP) and the dystrophin associated protein complex (DAPC) play important roles not only in muscle but in CNS and other non-muscle tissues. The laboratory of Alvaro Rendon (Strasbourg-Cedex-France) has been carrying studies in retina, which is considered as a structural model of the CNS. DMD gene mutations generate in DMD patients and mdx3cv mice strain a clear and defined abnormal electroretinogram (ERG). The main aim is to elucidate the function of the dystrophins and the DAPC in the retina. This might not only help us to understand information processing in the CNS but might also lead to better ways of approaching the muscle therapy of DMD patients. They identified four DMD gene products in rat retina: the 427 kDa dystrophin (Dp427), Dp260, Dp140 and Dp71. Their study was focused on the determination of their cellular localization. They showed that Dp260 was expressed in photoreceptor cells and Dp71 in Müller glial cells. They have characterized in Müller cells the presence of the DAPC, namely alpha and beta-dystroglycan, delta and gamma-sarcoglycans and alpha-1 syntrophin. They also show that beta-dystroglycan is associated with dystrobrevin-1 and PSD (Post Synaptic Derivatives)-93. By overlay experiments they also found that Dp71 and alpha-dystroglycan from Müller cells could bind to actin and laminin, respectively. These data suggest that the DAPs complex may participate in both structural and signalling functions in Müller cells. Nevertheless, the type as well as the cellular distribution of DAPs (but β-dystroglycan) in mouse retina is still unknown as well as how mdx3cv mutation might affect the complex dystrophin-DAPs. To this end they characterized the expression and localization of DMD gene products and DAPC. They findings indicated that only the dystroglycan complex is affected by mdx3cv mutation, specifically at the outer plexiform layer [[23]Newey S.E. Benson M.A. Ponting C.P. Davies K.E. Blake D.J. Alternative splicing of dystrobrevin regulates the stoichiometry of syntrophin binding to the dystrophin protein complex.Curr Biol. 2000; 10: 1295-1298Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. To clarify the importance of Dp71 they examined the ERG of Dp71 knockout mice [[24]Blake D.J. Hawkes R. Benson M.A. Beeslly P.W. Different dystrophin-like complexes are expressed in neurons and glia.J Cell Biol. 1999; 147: 645-658Crossref PubMed Scopus (206) Google Scholar] as well as the repercussion of the absence of this protein on the localization of members of the DAPC. The ERGs studies did not reveal significant differences either in implicit time or in the b-wave amplitude with respect to the wild strain. Since replacing its first and unique exon with a beta-gal reporter gene specifically inactivated the expression of Dp71, they therefore could evaluate by this mean the expression of Dp71. They found an inner limiting membrane (ILM) localization. The analysis of the localization of members of the DAPC indicates that only the dystroglycan complex was affected at the ILM. Interestingly, the absence of Dp71 seems to affect exclusively the localization of beta-dystroglycan without any effect on alpha-dystroglycan. In summary, it is clear from the comparison of the observations reported above in Dp71 knock-out mice and the fact that neither mdx (lacking dystrophin) nor Dp260 knock-out mice present a reduction in the b-wave amplitude, that is only the mdx3cv mutation with a severe reduction of all the dystrophin gene products that affects the ERG. In the last part of the workshop some of the neuromuscular disorders different from DMD and Becker muscular dystrophy have been discussed. Dr K. Murphy (London-United Kingdom) presented a review of the brain effects of myotonic dystrophy. MD is the most common form of adult muscular dystrophy; it is a pleiotropic autosomal dominant disease involving skeletal muscles, lens, heart, lungs, gastrointestinal tract, bone, skin, CNS and PNS (peripheral nervous system) [[25]Aleman V. Osorio B. Chavez O. Rendon A. Moenet D. Martinez D. Subcellular localization of Dp71 dystrophin isoforms in cultured hippocampal neurons and forebrain astrocytes.Histochem Cell Biol. 2001; 115: 243-254PubMed Google Scholar]. The disorder is caused by an amplification of an unstable trinucleotide (CTG) repeat in the 3′-untraslated region of a transcript encoding a serine/threonine kinase (DMPK) [[26]Sarig R. Mezger-Lallemand V. Gitelman I. et al.Targeted inactivation of Dp71, the maj" @default.
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- W2151985655 title "Report of the 95th European Neuromuscular Centre (ENMC) sponsored International Workshop Cognitive Impairment in Neuromuscular Disorders, Naarden, The Netherlands, 13–15 July 2001" @default.
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