Cloning of the mouse dysferlin gene and genomic characterization of the SJL-Dysf mutation

Vafiadaki, Elizabeth; Reis, André; Keers, Sharon; Harrison, Roger W.; Anderson, Louise V.B.; Raffelsberger, Thomas; Ivanova, Silva; Höger, Harald; Bittner, Reginald E.; Bushby, Kate; Bashir, Rumaisa

doi:10.1097/00001756-200103050-00039

Cited by 55 publications

(43 citation statements)

References 12 publications

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“…SJL mice were developed at the Jackson Laboratory in 1955 from 30 generations of repeated brother and sister matings from descendants of three different sources of Swiss Webster mice (20). Among other traits, these mice have a lateonset form of muscular dystrophy, owing to a mutation in the gene encoding Dysferlin, a muscle protein (21,22). Muscle weakness becomes apparent after 6 months of age.…”

Section: Discussionmentioning

confidence: 99%

Accelerated Fatty Acid Oxidation in Muscle Averts Fasting-induced Hepatic Steatosis in SJL/J Mice

Guan¹,

Goldstein

Brown

et al. 2009

Journal of Biological Chemistry

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The accumulation of triglycerides (TG) in the liver, designated hepatic steatosis, is characteristically associated with obesity and insulin resistance, but it can also develop after fasting. Here, we show that fasting-induced hepatic steatosis is under genetic control in inbred mice. After a 24-h fast, C57BL/6J mice and SJL/J mice both lost more than 20% of body weight and ϳ60% of total body TG. In C57BL/6J mice, TG accumulated in liver, producing frank steatosis. In striking contrast, SJL/J mice failed to accumulate any hepatic TG even though they lost nearly as much adipose tissue mass as the C57BL/6J mice. Mice from five other inbred strains developed fastinginduced steatosis like the C57BL/6J mice. Measurements of the uptake of free fatty acids (FA) in vivo and in vitro demonstrated that SJL/J mice were protected from steatosis because their heart and skeletal muscle took up and oxidized twice as much FA as compared with C57BL/6J mice. As a result of this muscle diversion, serum-free FA and ketone bodies rose much less after fasting in SJL/J mice as compared with C57BL/6J mice. When livers of SJL/J and C57BL/6J mice were perfused with similar concentrations of FA, the livers took up and esterified similar amounts. We conclude that SJL/J mice express one or more variant genes that lead to enhanced FA uptake and oxidation in muscle, thereby sparing the liver from FA overload in the fasting state.Liver and adipose tissue coordinate metabolic responses to oscillations in nutrient availability (1, 2). In the postprandial state, the liver secretes triglycerides (TG) 4 into the blood in very low-density lipoproteins (VLDL). In adipose tissue, lipoprotein lipase hydrolyzes the TG, producing fatty acids (FA) and monoglycerides that enter fat cells for reesterification and storage as TG (1). The activity of adipose tissue lipoprotein lipase is enhanced by the postprandial rise in insulin. At the same time, insulin inhibits lipolysis of stored TG in fat cells, assuring that the TG will be retained in the cells (3).Under fasting conditions, insulin falls and the inhibitory effect of insulin on adipose tissue lipolysis is diminished. The released FA enters the blood and is used as an energy source in liver, heart, and skeletal muscle. In the liver, excess FA are either re-esterified into TG for intracellular storage or oxidized and secreted as ketone bodies, which become the main energy source for the brain. In skeletal muscle during fasting, FA are oxidized to CO 2 (1, 2).We (4 -6) and others (7) previously reported that livers of mice accumulate large amounts of TG after fasting for 6 -24 h. In the current study, we screened 7 strains of inbred mice to study the genetic control of fasting-induced hepatic TG accumulation. Mice from 6 of 7 strains exhibited fasting-induced fatty liver. In the unique mouse strain (SJL/J), hepatic TG failed to accumulate after a 24-h fast even though the SJL/J mice lost amounts of body weight and adipose tissue that were similar to those of the other 6 strains. To trace the mechanism fo...

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Section: Discussionmentioning

confidence: 99%

Accelerated Fatty Acid Oxidation in Muscle Averts Fasting-induced Hepatic Steatosis in SJL/J Mice

Guan¹,

Goldstein

Brown

et al. 2009

Journal of Biological Chemistry

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“…The SJL/J mouse harbors a splice site mutation that results in a deletion corresponding to human exon 45 (6). SJL/J mice have long served as a model for autoimmune diseases, such as experimental allergic encephalomyelitis and myositis.…”

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confidence: 99%

Increased Susceptibility to Complement Attack due to Down-Regulation of Decay-Accelerating Factor/CD55 in Dysferlin-Deficient Muscular Dystrophy

Wenzel

Zabojszcza

Carl

et al. 2005

The Journal of Immunology

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Dysferlin is expressed in skeletal and cardiac muscles. However, dysferlin deficiency results in skeletal muscle weakness, but spares the heart. We compared intraindividual mRNA expression profiles of cardiac and skeletal muscle in dysferlin-deficient SJL/J mice and found down-regulation of the complement inhibitor, decay-accelerating factor/CD55, in skeletal muscle only. This finding was confirmed on mRNA and protein levels in two additional dysferlin-deficient mouse strains, A/J mice and Dysf−/− mice, as well as in patients with dysferlin-deficient muscular dystrophy. In vitro, the absence of CD55 led to an increased susceptibility of human myotubes to complement attack. Evidence is provided that decay-accelerating factor/CD55 is regulated via the myostatin-SMAD pathway. In conclusion, a novel mechanism of muscle fiber injury in dysferlin-deficient muscular dystrophy is demonstrated, possibly opening therapeutic avenues in this to date untreatable disorder.

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“…Different threedimensional shapes adopted by these protein domains allow ferlin members to interact with binding partners; therefore, C2 structural data would be very informative (18,19). Within the ferlin family, dysferlin is particularly well conserved among mammals (90% similarity between human and mouse [20,21]) and contains seven C2 domains. Multiple copies of C2 domains are frequently found in this particular protein family (22).…”

Section: Introductionmentioning

confidence: 99%

Translational Research and Therapeutic Perspectives in Dysferlinopathies

Barthélémy

Wein

Krahn

et al. 2011

Mol Med

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Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene, encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B) and the second most common being LGMD. Symptoms generally appear at the end of childhood and, although disease progression is typically slow, walking impairments eventually result. Dysferlin is a modular type II transmembrane protein for which numerous binding partners have been identified. Although dysferlin function is only partially elucidated, this large protein contains seven calcium sensor C2 domains, shown to play a key role in muscle membrane repair. On the basis of this major function, along with detailed clinical observations, it has been possible to design various therapeutic approaches for dysferlin-deficient patients. Among them, exon-skipping and minigene transfer strategies have been evaluated at the preclinical level and, to date, represent promising approaches for clinical trials. This review aims to summarize the pathophysiology of dysferlinopathies and to evaluate the therapeutic potential for treatments currently under development.

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Cloning of the mouse dysferlin gene and genomic characterization of the SJL-Dysf mutation

Cited by 55 publications

References 12 publications

Accelerated Fatty Acid Oxidation in Muscle Averts Fasting-induced Hepatic Steatosis in SJL/J Mice

Accelerated Fatty Acid Oxidation in Muscle Averts Fasting-induced Hepatic Steatosis in SJL/J Mice

Increased Susceptibility to Complement Attack due to Down-Regulation of Decay-Accelerating Factor/CD55 in Dysferlin-Deficient Muscular Dystrophy

Translational Research and Therapeutic Perspectives in Dysferlinopathies

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