Dysferlin and Animal Models for Dysferlinopathy

Kobayashi, Kinji; Izawa, Takeshi; Kuwamura, Mitsuru; Yamate, Jyoji

doi:10.1293/tox.25.135

Cited by 43 publications

(26 citation statements)

References 84 publications

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“…Loss of dysferlin from the plasma membrane of muscle fibers leads to abnormalities in vesicular trafficking and membrane repair (Kobayashi et al, 2012). Moreover, freshly isolated monocytes of dysferlinopathy patients show deregulated expression of fibronectin and fibronectin-binding integrins which is recapitulated by transient knockdown of dysferlin in the human monocytic cell line, THP1.…”

Section: Introductionmentioning

confidence: 99%

Dysferlin is essential for endocytosis in the sea star oocyte

Oulhen

Onorato

Ramos

et al. 2014

Developmental Biology

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Dysferlin is a calcium-binding transmembrane protein involved in membrane fusion and membrane repair. In humans, mutations in the dysferlin gene are associated with muscular dystrophy. In this study, we isolated plasma membrane-enriched fractions from full-grown immature oocytes of the sea star, and identified dysferlin by mass spectrometry analysis. The full-length dysferlin sequence is highly conserved between human and the sea star. We learned that in the sea star Patiria miniata, dysferlin RNA and protein are expressed from oogenesis to gastrulation. Interestingly, the protein is highly enriched in the plasma membrane of oocytes. Injection of a morpholino against dysferlin leads to a decrease of endocytosis in oocytes, and to a developmental arrest during gastrulation. These results suggest that dysferlin is critical for normal endocytosis during oogenesis and for embryogenesis in the sea star and that this animal may be a useful model for studying the relationship of dysferlin structure as it relates to its function.

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Section: Introductionmentioning

confidence: 99%

Dysferlin is essential for endocytosis in the sea star oocyte

Oulhen

Onorato

Ramos

et al. 2014

Developmental Biology

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“…Although the Dysf mutation in the A/J strain appears to be unique to this strain (a 5-6kb ETn retrotransposon inserted into intron 4) [13], the SJL/J (SJ) inbred strain has a splicesite mutation in Dysf, resulting in a markedly decreased protein level [14]. Like the A/J strain, the SJ strain is also considered a naturally occurring animal model for dysferlinopathy [15].…”

Section: Improving the Rate Of Affected Recombinant Micementioning

confidence: 99%

Heart Disease in a Mutant Mouse Model of Spontaneous Eosinophilic Myocarditis Maps to Three Highly Significant Loci

Zimmermann

Gibbons

Homan

et al. 2019

Preprint

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Background: Heart disease (HD) is the major cause of morbidity and mortality in patients with hypereosinophilic diseases. Due to a lack of adequate animal models, our understanding of the pathophysiology of eosinophil-mediated diseases with heart complications is limited. We have discovered a mouse mutant, now maintained on an A/J inbred background, that spontaneously develops hypereosinophilia in multiple organs. Cellular infiltration into the heart causes an eosinophilic myocarditis, with affected mice of the mutant line (i.e., A/J HD ) demonstrating extensive myocardial damage and remodeling that leads to HD and premature death, usually by 15-weeks old. Maintaining the A/J HD line for many generations established that the HD trait was heritable and implied the mode of inheritance was not too complex. Backcross and intercross populations generated from mating A/J HD males with females from four different inbred strains produced recombinant populations with highly variable rates of affected offspring, ranging from none in C57BL/6J intercrosses, to a few mice with HD using 129S1/SvImJ intercrosses and C57BL/6J backcrosses, but nearly 8% of intercrosses and >17% of backcrosses from SJL/J related populations developed HD. Linkage analyses of these SJL/J derived recombinants identified three highly significant loci: a recessive locus mapping to distal chromosome 5 (LOD=4.88; named Emhd1 for eosinophilic myocarditis to heart disease-1); and two dominant variants mapping to chromosome 17, one (Emhd2; LOD=7.51) proximal to the major histocompatibility complex, and a second (Emhd3; LOD=6.89) that includes the major histocompatibility region. Haplotype analysis identified the specific crossovers that defined the Emhd1 (2.65Mb), Emhd2 (8.46Mb) and Emhd3 (14.59Mb) intervals. These results indicate the HD trait in this mutant mouse model of eosinophilic myocarditis is oligogenic with reduced penetrance, due to multiple segregating variants and possibly additional genetic or nongenetic factors. The A/J HD mouse model represents a unique and valuable tool to understand the interplay of causal factors that underlie the pathology of this newly discovered eosinophilassociated disease with cardiac complications.

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“…Although the Dysf mutation in the A/J strain appears to be unique to this strain (a 5-6kb ETn retrotransposon inserted into intron 4) [ 13], the SJL/J (SJ) inbred strain has a splice-site mutation in Dysf, resulting in a markedly decreased protein level [ 14]. Like the A/J strain, the SJ strain is also considered a naturally occurring animal model 8 for dysferlinopathy [ 15]. Consequently, all mice deriving from crosses of the SJ and A/J HD strains will carry two mutated copies of the Dysf gene.…”

Section: Replicating the Trait In Recombinantsmentioning

confidence: 99%