Table 2 - uploaded by Donald Roy Love
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List of genes on human chromosome 6 long arm also localised to mouse chromosome 10. IFNGR1/Ifgr is the interferon gamma receptor
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We have localised a dystrophin-related autosomal gene called DMDL (Duchenne muscular dystrophy-like) to human chromosome 61q24 by in situ hybridisation. Using restriction fragment length polymorphism analysis in two mouse species, we have localised the homologous gene Dmdl in the mouse to chromosome 10 proximal to the Myb oncogene. A neuromuscular...
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Context 1
... have localised DMDL in man to band 6q24, and the homologous gene in the mouse, Dmdl, to chromosome 10 proximal to the oncogene Myb, which is localised to bands A1-B4 (Lyon 1989). These data establish the exis- tence of a conserved linkage group between the distal long arm of chromosome 6 in man and the proximal half of mouse chromosome 10 ( Table 2). The size of this seg- ment must exceed 23 cM, i.e. the distance between Myb and Dmdl in the mouse; this makes it one of only 13 con- served autosomal segments between man and mouse known to exceed 20 cM ( Searle et al. 1989). ...
Citations
... Utrophin is an autosomal paralogue of dystrophin. The utrophin gene is located on the human chromosome 6q24 and the mouse chromosome 10 (Buckle, Guenet et al. 1990) and its transcription is controlled by two differentially regulated promoters, A and B. These two promoters drive the transcription of two different mRNA isoforms that are translated in two full-length utrophin proteins, A-utrophin and B-utrophin (Figure 4). A and B-utrophin proteins have a 395kDa molecular weight and they share 80% amino acid identity with dystrophin (Tinsley, Blake et al. 1992). ...
Patients living with Duchenne and Becker muscular dystrophy are characterised respectively by the loss of a functional dystrophin protein and the expression of a mutant dystrophin protein. Dilated cardiomyopathy (DCM) is the major cause of death in these patients and the molecular mechanisms causing DCM in these patients are still not completely established. In fact, the cardiac disease is treated with cardioprotective drugs that delay but do not prevent DCM as a targeted treatment for the heart is still not available due to this lack of knowledge. Previous findings showed that exclusively in the heart, the dystrophin glycoprotein complex includes cavin-1, an essential protein for the biogenesis of caveolae. Caveolae in the heart are involved in mechanisms of cardio protection, cardiac contraction, and cardiac conduction. Key caveolae accessory proteins include cavin-2, -3 and -4. More importantly, caveolar protein mutations have been linked to cardiomyopathy. My PhD thesis investigates the molecular interactions between cardiac dystrophin and cavins that are important for cardiac function and are affected by dystrophin gene mutations. I have characterised the distribution of cavin proteins in mouse, rat and dog models of Duchenne muscular dystrophy (DMD) comparing this distribution in explanted human heart and discovered that cavin-1 and -4 cardiac localisation is conserved across these different species. I have investigated the effect of the loss of full-length dystrophin in DMD mouse, rat and dog models finding different levels of disruption of cavin-1 and -4 that could be attributed by the expression of shorter dystrophin isoforms in these animal models. I have also tested the ability of five different micro and mini-dystrophin (one of them is currently used in a clinical trial) constructs in restoring the physiological cardiac localisation of cavin-1 and -4 finding that none of them is able to do this. Overall, my findings suggest that the cardiac localisation of cavins is dependent on the expression of dystrophin at the cardiomyocyte membrane and that the cavin binding domain could reside in the distal part of the dystrophin protein. This knowledge suggests new roles of dystrophin in the heart and could be useful for the design of the next gene therapy constructs and for the development of targeted cardiac therapies.
... Utrophin cDNA (13kb) is encoded by an ~ 1Mb autosoml gene. This gene was found to be located on chromosome 6 of human (chromosome 10 of mouse) [35,36]. Utrophin gene contains multiple exons spanning large region of genome. ...
Duchenne Muscular Dystrophy (DMD) is one the most frequent genetic disorder that affects 1 in every 3500 males worldwide. This fatal neuromuscular disorder arises from the defects in the protein, called dystrophin. The dystrophin coding gene is the largest known gene and present in X chromosome. Several strategies, ranging from cell based therapy to small RNA mediated exon skipping have been proposed as an effective therapy for this disease. Experiments in mice model have shown that upregulation of utrophin, the autosomal homologue of dystrophin can compensate dystrophin deficiency and ameliorate the dystrophic phenotype. Therefore utrophin has also been considered as a potent target for development of strategies against DMD. In the current review we describe different therapeutic approaches for DMD along with challenges they have to overcome.
... Utrophin cDNA (13kb) is encoded by an ~ 1Mb autosoml gene. This gene was found to be located on chromosome 6 of human (chromosome 10 of mouse) [35,36]. Utrophin gene contains multiple exons spanning large region of genome. ...
... This autosomal protein was identified in 1989 [60] due to its large homology with dystrophin, and it was named utrophin because of its ubiquitous tissue expression as compared to dystrophin [61]. The gene is localized on human chromosome 6q24 [62] and on mouse proximal chromosome 10 [61]. This large 900 kb gene encodes a 13 kb transcript of 74 exons that predicts a full-length protein of 395 kDa, which is therefore smaller than dystrophin. ...
Two decades of molecular, cellular, and functional studies considerably increased our understanding of dystrophins function and unveiled the complex etiology of the cognitive deficits in Duchenne muscular dystrophy (DMD), which involves altered expression of several dystrophin-gene products in brain. Dystrophins are normally part of critical cytoskeleton-associated membrane-bound molecular scaffolds involved in the clustering of receptors, ion channels, and signaling proteins that contribute to synapse physiology and blood-brain barrier function. The utrophin gene also drives brain expression of several paralogs proteins, which cellular expression and biological roles remain to be elucidated. Here we review the structural and functional properties of dystrophins and utrophins in brain, the consequences of dystrophins loss-of-function as revealed by numerous studies in mouse models of DMD, and we discuss future challenges and putative therapeutic strategies that may compensate for the cognitive impairment in DMD based on experimental manipulation of dystrophins and/or utrophins brain expression.
... L'utrophine a été identifiée en 1989 (Love et al., 1989). Son gène est localisé sur le chromosome 6 et donne lieu a une protéine de 395kDa, ainsi qu'à plusieurs formes courtes (Buckle et al., 1990;Tinsley et al., 1992). L'utrophine présente 80% d'homologie avec la dystrophine, particulièrement aux extrémités N et C terminales (Tinsley et al., 1992). ...
Duchenne muscular dystrophy is a muscular degenerative disease caused by the absence of dystrophin. Dystrophin function and the causes of muscle degeneration in its absence are still not known.
I combined studies in the Caenorhabditis elegans and murine animal models of this disease to elucidate the mechanisms of muscle degeneration.
We demonstrated that the calcium-dependant potassium channel, SLO-1, and the syntrophin homologue, STN-1, are functionally linked to the C. elegans homologue of dystrophin, DYS-1. We ran a genome-wide screen in search of suppressor genes of muscular degeneration. We showed that the protein degradation pathways and several kinases are involved in muscular degeneration in C. elegans. In parallel, I participated to the search of molecules reducing muscle degeneration in C. elegans, and then in mdx mice. We confirmed the beneficial effect of the activation of the serotonergic pathway on the muscular degeneration of mdx mice.
... The amino-terminus and a region in the rod domain of dystrophin and utrophin bind directly to cortical actin [57]. The full-length utrophin isoform Up395 represents an autosomal homologue of the dystrophin isoform Dp427 [11,40]. In humans, its gene is located on chromosome 6. ...
Primary abnormalities in the dystrophin gene underlie x-linked muscular dystrophy. However, the absence of the dystrophin isoform Dp427 does not necessarily result in a severe dystrophic phenotype in all muscle groups. Distal mdx muscles, namely extraocular and toe fibres, appear to represent a protected phenotype in muscular dystrophy. Thus, a comparative analysis of affected versus naturally protected muscle cells should lead to a greater knowledge of the molecular pathogenesis of inherited neuromuscular disorders. Furthermore, rationalising the protective cellular mechanisms might help in developing new treatment strategies for muscular dystrophy. The rescuing of extraocular and toe muscle fibres has previously been attributed to the special protective properties of fast-twitching small-diameter fibres. More recent biochemical studies have shown that the up-regulation of the autosomal dystrophin homologue named utrophin and the concomitant rescue of dystrophin-associated glycoproteins also plays an important role in the mechanical stabilisation of Dp427-deficient fibres. This result is mirrored in the dystrophic mdx brain where the dystrophin isoform Dp71 seems to be responsible for the preservation of the dystroglycan complex. It is envisaged that future proteomics-based comparisons of naturally protective extraocular, toe and brain tissues with severely affected skeletal muscle fibres will greatly add to our general understanding of the pathophysiology of muscular dystrophy.
... 138 Utrophin is translated from a 13 kb transcript on chromosome 6 (q24) in human beings and chromosome 10 in mice. 139 Utrophin expression has a widespread sarcolemmal distribution in human and mouse dystrophic muscle. 140,141 Utrophin deficiency in mdx mice exacerbates the mdx phenotype to produce a model that more accurately represents human DMD. ...
The development of therapeutic strategies that overcome the unique problems posed by Duchenne muscular dystrophy (DMD) has lead to the development of many contemporary approaches to human disease in general. Various treatment approaches have been explored--such as pharmacological therapies and cell-based, cytokine, and genetic therapies--that are all targeted to specific features of dystrophic DMD muscle pathology. In genetic therapies, the large size of the dystrophin gene has necessitated the development and use of novel functional minidystrophin and microdystrophin genes, muscle-specific promoter systems, and gutted adenoviral systems. In addition to these well defined viral strategies, plasmid vectors and the upregulation of utrophin (a dystrophin homologue) have potential. Various novel genetic approaches--such as antisense-mediated exon skipping, gene correction, and new cytokine approaches--are also being developed. Together these exciting developments bring an effective treatment for DMD closer than ever before.
... Alternate splicing at the 3' end of dystrophin mRNA results in the generation of different isoforms of full-length dystrophin [36], as well as the shorter Dp71 isoform, the latter modifications resulting in the transposition of Dp71 from the subsarcolemmal region to the cytoplasm [43]. A chromosome 6-encoded autosomal homologue of dystrophin, termed dystrophin-related protein or utrophin, contains high sequence similarity to dystrophin [14,65]. A 395 kDa submembranous protein, utrophin is predominantly located at the myotendinous and neuromuscular junctions, where it functions to anchor nicotinic acetylcholine receptors through interactions with a surface glycoprotein complex [75,92]. ...
... It is highly homologous to dystrophin sharing a 73% homology with dystrophin's C-terminal at the amino acid level which is increased to 83% if conservative amino acid substitutions are taken into consideration (Love et al. 1989;Tinsley et al. 1992). Utrophin is encoded by a large (1Mb) gene located on human chromosome 6q24 and mouse chromosome 10 (Love et al 1989;Buckle et al 1990;Khurana et al 1990). ...
Duchenne and Becker muscular dystrophies (DMD/BMD) are caused by mutations in the dystrophin gene. DMD is also associated with a variable degree of mental impairment. Several dystrophin transcripts are expressed in the brain including a novel transcript (P-type dystrophin) expressed specifically in Purkinje cells; its expression is controlled by an alternative promoter. This study shows that the P-type mRNA is also expressed in skeletal and cardiac muscle but not in smooth muscle. Its first exon encodes a specific, short amino terminus that is highly conserved in mammals and to a lesser extent in chicken. The nucleotide sequence of the P-type first exon and putative promoter region is also conserved. In mice, the 5'-end of the P-type transcript was found to be structurally diverse arising from alternative splicing events at the 5'-UTR. This may occur separately or in combination with insertion of a part of intron I resulting in premature termination of translation. There are multiple transcription initiation sites, the predominant one being conserved in human and mouse. Moreover, alternative usage of ATG codons may result in alternative N-termini in rodents or short upstream open reading frames in other species. Several regulatory elements are conserved in different species. The TATA box found in human sequence is not conserved and is outside the region that directed CAT reporter gene expression in differentiated myotubes in culture.
... Patients with Fukuyama muscular dystrophy also have a deficiency in expression of the α2 laminin chain. Linkage analysis of these patients shows that this disease does not localize to the laminin α2 chain (Matsumura et al., 1993a;Toda et al., 1993;Buckel et al., 1990), or to the α7 integrin (Wang et al., 1995) or the β1 integrin chain genes (Goodfellow et al., 1989). A common theme in all of these myopathies is that abnormalities in the association of muscle fibers with the basal lamina result in structural defects that lead to the loss of muscle integrity and function. ...
The alpha7beta1 integrin is the primary laminin receptor on skeletal myoblasts and adult myofibers. It has distinct functions during muscle development and contributes to muscle structural integrity. We have studied this integrin in cases where expression of dystrophin or laminin are compromised. Immunofluorescence demonstrates an increase in alpha7beta1 in patients with Duchenne muscular dystrophy and in mdx mice that lack dystrophin. Analysis of RNA from mdx mice and from patients with Duchenne and Becker muscular dystrophies indicates that the increase in the alpha7beta1 integrin is regulated at the level of alpha7 gene transcription. In contrast, the levels of alpha7beta1 integrin are severely diminished in patients with laminin alpha2 chain congenital dystrophy muscular dystrophy and in dy/dy mice that also do not make the alpha2 laminin chain. Analysis of RNA from the hindlimbs of dy/dy mice demonstrated that in the absence of laminin alpha7 gene transcription is inhibited and limited to specific alternatively spliced isoforms. We suggest that the increased expression of alpha7beta1 integrin in the absence of dystrophin compensates for the reduced dystrophin-mediated linkage of fibers with the basal lamina and modulates the development of pathology associated with these diseases. The decrease in alpha7beta1 integrin and its transcripts in the absence of laminin likely contributes to the severe myopathy that results from laminin alpha2 chain deficiency and suggests that laminin-2 regulates expression of the alpha7 integrin gene. The role of the alpha7beta1 integrin in muscle integrity also suggests that compromised expression of this receptor may underlie as yet undefined myopathies.
