Function and Genetics of Dystrophin and Dystrophin Related Proteins in Muscle

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Function and Genetics of Dystrophin and Dystrophin-Related Proteins in Muscle

DEREK J. BLAKE, ANDREW WEIR, SARAH E. NEWEY, AND KAY E. DAVIES

Function and Genetics of Dystrophin and Dystrophin-Related Proteins in Muscle

III. Dystrophin: Gene and Protein

IV. The mdx Mouse and Other Dystrophin-Deficient Animals 296

V. Pathophysiology of Dystrophin-Deficient Muscle

VI. Dystrophin-Associated Protein Complex

  Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complexthat connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complexin normal muscle function.

VII. The Dystrophin Paralog Utrophin

  The vast majority of DMD mutationsresult in the complete absence of dystrophin, whereas the presence of low levels of a truncated protein is seen inBMD patients. A sec- ondary sign of muscle fiber necrosis, at least in the earlystages of the dystrophinopathies, is the active regenera- tion of muscle to replace or repair lost or damaged fibers(438).

A. Clinical Progression of Duchenne and Becker Muscular Dystrophies

  DYSTROPHIN AND DYSTROPHIN-RELATED PROTEINS 293 tually, the regenerative capacity of the muscles is lost and tion was confirmed using DNA markers (123), and the muscle fibers are gradually replaced by adipose and fi- disease was shown to be allelic with a milder disease ofbrous connective tissue, giving rise to the clinical appear- similar clinical course, BMD (273). The DMD gene is the largest de-and ultimately muscle weakness.scribed, spanning ⬃2.5 Mb of genomic sequence (Fig. 1) (98, 355) and is composed of 79 exons (98, 355, 417).

III. DYSTROPHIN: GENE AND PROTEIN

was found to be predominantly expressed in skeletal and cardiac muscle with smaller amounts in brain and cov-

A. Gene Sequence ered a large genomic region (280, 351, 354). The protein

  The study of suchmutations has revealed the importance of a number of the structural domains of dystrophin and facilitated the de-sign of dystrophin “mini-genes” for gene therapy ap- proaches (reviewed in Ref. 9). Thisobservation suggests that the rod domain acts as a spacer between the actin binding domain and the cysteine-richand COOH-terminal domains of dystrophin, and trunca- tion of this region merely shortens the bridge betweenthese two functional regions without adversely affecting the function of the protein.

E. Mutations in DMD

  Another reported substitution of an aspartateresidue to a histidine residue at position 3335 is also thought to affect the ␤-dystroglycan binding site, and although therewas normal localization and amounts of dystrophin de- tected, a severe phenotype resulted (184). Finally, cases of X-linked cardiomyopathy are caused by mutations in the DMD gene that abolish the cardiacgene expression of dystrophin, while retaining expression in skeletal muscle.

IV. THE MDX MOUSE AND OTHER DYSTROPHIN-DEFICIENT ANIMALS

  This observation, sub- sequently confirmed, together with the high levels ofseveral cytosolic proteins in the blood of patients with DMD, gave rise to the theory that the primary pathologyof DMD muscle might be an abnormal fragility and leak- iness of the cell membrane (349, 422). Although no equiv-alent to the delta lesion has been found in the mdx mouse (120, 481) or GRMD dog (489), there is good evidence thatdystrophin-deficient muscle is characterized by increased permeability to macromolecules flowing in and out of thecell and that this abnormal permeability is made worse by mechanical stress.

C. The Dystrophin-Deficient Cat

V. PATHOPHYSIOLOGY OF DYSTROPHIN-DEFICIENT MUSCLE

A. Abnormalities of the Muscle Cell

1. Membrane structure and function

  Part of the diffi- culty may be methodological, and the issues of calibra-tion, altered handling of the dye by dystrophin-deficient cells, variable subcellular compartmentalization of differ-ent dyes, and techniques for introducing the dye into cells have been raised (182, 183, 236). In 1988, two groups reported the use of this tech- nique to show that the [Ca 2⫹]i CA2⫹ There is thus good evidence that dystrophin-deficient muscle contains fibers that allow ingress of moleculesnormally excluded from the cytoplasm and that this ten- dency is enhanced after muscle has been put under me-chanical stress.

CALCIUM FLUXES

FLOWS OF CALCIUM INTO THE CELL

  Although this second channel activity could not be shown to occur in mdx myofibers, the au-thors showed that in this situation the open probability of the first kind of mechanosensitive channel was greater inmdx than control fibers (164, 217). Are theredifferences in regional [Ca ⫹channels with the patch clamp in both the cell-attached and inside-out configurations, they esti-mated that [Ca 2⫹] between cells with and without dystrophin that could be missed because of this?

FLUXES INTO THE SR

  Nordoes it seem that the relocalization of nNOS from sarco- lemma to cytoplasm (where it could conceivably havedeleterious effects) contributes to the pathology; mdx DYSTROPHIN AND DYSTROPHIN-RELATED PROTEINS 301 However, evidence is available that the lack of nNOS in dystrophin-deficient muscle may still play a part in thepathological process. Although it has been demon-strated recently that populations of cells exist in other tissues that can gain access to muscle via the circulationand contribute to muscle regeneration, satellite cells are responsible for the predominant part of muscle regener-ation (154).

C. Summary

  Thus the DPC can be thought of as glycan gene is composed of only two exons, and there is a scaffold connecting the inside of a muscle fiber to the no evidence of alternative splicing, although several gly-outside.coforms are produced (245). The structure of this region of dystrophin shows that dystroglycan forms contacts with both the WW do-main and EF hands of dystrophin, emphasizing the func- tional importance of both of these domains to the dystro-phin family of related proteins.

3. Proteins that potentially modify the disease state in muscular dystrophy

  Can replace laminin-2 in the dy/dy mouse model of MD 350Utrophin Can functionally replace dystrophin restoring the DPC to the sarcolemma 474, 477Fukutin Mutated in FCMD 7 204Presented is a list of proteins whose expression can alter the composition or function of the DPC. Typically, the loss ofone sarcoglycan results in the absence or severe reduc- tion in the remaining components of the sarcoglycan com-plex, although recent studies of patient muscle biopsies have demonstrated a variation in the pattern of sarcogly-can complex disruption (reviewed in Ref. 71).

C. Sarcoglycan Complex

  These data suggest that sarcospan is notrequired for the normal function of the DPC and is not crucial in the formation and stabilization of the sarcogly-can complex, but it may be the case that another protein, perhaps another tetraspan protein, can compensate forthe loss of sarcospan (290). As predicted, no DYSTROPHIN AND DYSTROPHIN-RELATED PROTEINS 309 Although it has been noted that all the sarcoglycan- deficient animal models share a number of features, in-cluding muscular dystrophy and a secondary reduction in the localization of other components of the sarcoglycancomplex, experiments by Hack and colleagues (207, 208) have demonstrated that loss of an individual sarcoglycancan have apparently different mechanical consequences for the muscle fibers.

F. Dystrobrevin

  Comparison of the levels of cGMP in normal, ␣-dystrobrevin-deficient, and nNOS-deficient mice showedthat the ␣-dystrobrevin mouse had no significant increase in the levels of cGMP in resting compared with electri-cally stimulated muscle. The Utrophin GeneTwo years after the discovery of dystrophin a frag- ment of cDNA derived from fetal muscle was describedthat was similar to but distinct from the COOH terminus of the DMD gene (306).

B. Utrophin Localization

  Functional Domains and Binding Partners: Interactions of the COOH Terminus of UtrophinThe primary structures of the COOH termini of utro- phin and dystrophin are also very similar, and this sug-gested that utrophin too might be able to bind members of the DPC (475). There is much in vitro and in vivo evidenceto show that utrophin can bind ␤-dystroglycan (320, 480), ␣-dystrobrevin-1 (389), and the syntrophins (285, 387) andalso that it can form part of a complex that includes the sarcoglycans (320).

H. Functional Studies: Dystrophin/Utrophin Null Mutants

  Given the interaction between syntrophin and nNOS in muscle and PSD-95 and nNOS in neurons, apossible role for this protein may be to regulate the association of nNOS with the DPC-like complex in C.elegans (59, 60). CONCLUSIONSThe identification of mutations in the dystrophin gene as the cause of DMD led the way for the positionalcloning of many other genes responsible for single gene disorders.

VERY RJ

  In situ localisation of single-stranded DNA breaks in nuclei of a subpopu-lation of cells within regenerating skeletal muscle of the dystrophic mdx mouse. Consequences of the combined defi- ciency in dystrophin and utrophin on the mechanical properties and myosin composition of some limb and respiratory muscles ofthe mouse.

INDGREN V

  Understanding dystrophinopathies: an inventory of the structural and functional consequences of the absence of dystro-phin in muscles of the mdx mouse. G AILLY P, B OLAND INE SW, F U M, B ERMUDEZ J, I M, F D, C HU JB, L F, V OLONTE evaluation of cytosolic calcium determination in resting muscle fibres from normal and dystrophic (mdx) mice.

ILKINSON RS, AND

  G IESELER K, M ARIOL MC, B ESSOU C, M of the mdx mouse, an animal model of the Duchenne muscular dystrophy: a review. Muscle fibre atrophy in critically ill patients is associated with the loss of myosin filaments and the presence oflysosomal enzymes and ubiquitin.

ISHIMURA T

  Localization of dystrophin isoform Dp71 to the inner limiting membrane of the retina suggests a unique functional con- tribution of Dp71 in the retina. The 2.0 A structure of the second calponin homology domain from the actin-binding region of the dystrophin homologue utro-phin.

ARBONETTO S

  G, L A,K IURU A, S AVONTAUS ML, G ILGENKRANTZ H, R ECAN D, C HELLY J, K APLANJC, C OVONE AE, A RCHIDIACONO N, R OMEO IECHTIGALLATI S, S CHNEI - DER V, B RAGA S, M OSER INDLOF M, K AARIAINEN H, D ARRAS BT, M URPHY P, F RANCKE U, C HENJD, M ORGAN G, D ENTON M, G REENBERG CR, W ROGEMANN K, B LONDENLAJ, V AN P AASSEN HMB, V ANOMMEN GJB, AND K UNKEL LM. Complete cloning of the Duchenne muscular dystrophy(DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals.

AULKNER JA

  A cysteine 3340 substitution in the dystroglycan-binding domain of dystrophin associated with Duchenne muscular dystro-phy, mental retardation and absence of the ERG b-wave. L IDOV HG, S ELIG S, AND S R, T NCKER N, M O, Y UCHS G, F ORRIS D, M ORNET UGIER D, Z, A EVY D, L Force and power output of fast and slow skeletal muscles from mdx mice 6 –28 mo old.

UBOWITZ V

  M ONES ENDRICK K AND NH, EEP CA, K at rest and after cholinergic stimulus is increased in cultured muscle cells fromDuchenne muscular dystrophy patients. Duchenne dystrophy: electron microscopic findings pointing to a basic or early abnormality in the plasmamembrane of the muscle fiber.

UDNICKI MA

  M A Increased expression of IGF-binding protein-5 in Duchenne mus- cular dystrophy (DMD) fibroblasts correlates with the fibroblast-induced downregulation of DMD myoblast growth: an in vitro analysis. Nature of the mononu- clear infiltrate and the mechanism of muscle damage in juveniledermatomyositis and Duchenne muscular dystrophy.

ILTON -J ONES

  P RESSMAR J, B RINKMEIER H, S EEWALD MJ, N AUMANN T, AND R Intracellular Ca 2⫹ RIOR AND TW, B ARTOLO C, P EARL DK, P APP AC, S NYDER PJ, S EDRA MS,B URGHES AH, AND D J, ENDELL C, S ERVIDEIS, P UCA AA, T ONALI P, P UCA GA, AND N MR, K RAMARCY NR, K UNKEL LM, S ANES JR, S EALOCK R, AND F ROEHNER SC. Localization of the DMDL gene-encoded dystro- phin-related protein using a panel of nineteen monoclonal antibod- ies: presence at neuromuscular junctions, in the sarcolemma ofdystrophic skeletal muscle, in vascular and other smooth muscles, and in proliferating brain cell lines.

UDEL R

  The relationship between perlecan and dystroglycan and its implication in the formation of the neuromuscular junction. Targeted inactivation of Dp71, the major non- muscle product of the DMD gene: differential activity of the Dp71promoter during development.

IDOV HG

ILLIS J-M, AND

  Contribution of the different modules in the utrophin carboxy- terminal region to the formation and regulation of the DAP com-plex. Glycoprotein- binding site of dystrophin is confined to the cysteine-rich domainand the first half of the carboxy-terminal domain.

IGRO V

  Is the maintainance of the C-terminus domain of dystrophin enough to ensure a milder Becker muscular dystrophy phenotype? Binding of the G domains of laminin alpha1 and alpha2 chains and perlecan to heparin, sulfatides, alpha-dystroglycan and several extracellularmatrix proteins.

OOPER BJ

  Dissociation of the complex of dystrophin and its associated proteins into several unique groups by n-octyl beta- ZAWA O AND Y, IZUNO H, D D. Tyrosine and serine phosphorylation of dystrophin and the 58-kDa protein in the postsynaptic mem-brane of Torpedo electric organ.

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