Mouse models of neuromuscular disorders

Duchenne muscular dystrophy (DMD) mouse models 

 

C57BL/10ScSn-Dmdmdx/J: A stop codon mutation in exon-23 of the dystrophin gene results in dystrophin deficiency. This is a widely used genetic and biochemical mouse model for DMD. The disease phenotype is mild. Skeletal muscle pathology develops around 3 weeks of age, with muscle weakness by 5-6 weeks. These mice are homozygous, and no genotyping is needed.  C57BL/10ScSnJ mice are wild-type controls for this model. We have systematically phenotyped this model at multiple age groups. Publication

 

D2.B10-Dmdmdx/J: C57BL/10-mdx mice were backcrossed to DBA/2J inbred mice for several generations by Jackson Labs, using a speed congenics approach to generate the DBA/2J-congenic strain (DBA/2J-mdx).  The skeletal muscle and cardiac phenotype is more severe than that of C57BL/10ScSn-Dmdmdx/J. This may be a useful model for preclinical drug testing. DBA2/J mice are the wild-type controls for this model. We have systematically phenotyped this model at multiple age groups. 

 

B6Ros.Cg-Dmdmdx-4Cv/J: This strain was generated through n-ethylnitrosourea (ENU) mutagenesis program. It has fewer revertant muscle fibers than the mdx strain in skeletal muscle. These mice exhibit histopathological features similar to mdx including fibrosis, fatty infiltration and necrosis in the diaphragm that progresses with age. 

 

MDX-52 mice: Developed by Dr. Takeda's group at NCNP, Japan, the MDX-23 mutation does not disrupt the expression of four other shorter isoforms that are also expressed from the dystrophin gene through differential promoter usage. The skeletal muscles are hypertrophic, and the muscles exhibit variations in fiber size, with evidence of necrosis and regeneration. C57BL/6 mice are the wild-type controls for this model.

 

Limb girdle muscular dystrophy (LGMD) 2B mouse models

 

A/J miceThis inbred strain contains a naturally occurring dysferlin mutation and was originally developed from a cross between a Cold Spring Harbor albino mouse and a Bagg albino mouse. The absence of the dysferlin protein results from an ETn retrotransposon (5-6kb) insertion in intron 4 of the dysferlin gene. Histological evidence of dystrophy is not seen until 4-5 months of age, and muscle weakness progresses slowly. The abdominal muscles are most severely affected, followed by proximal muscles and then distal muscles. We have systematically phenotyped this model at multiple age groups. 

 

SJL/J mice: Exon 45 is deleted in the mRNA as the result of a mutation in the 3’ splice junction in the dysferlin gene.  This deletion removes part of the fifth C2 domain (C2E) of the dysferlin protein.  Mild myopathic lesions can be seen histologically by around 4 weeks of age, and active myopathy by 6-8 months in the proximal muscle groups. In older mice (16 months) >50% of the muscle is replaced by fat.  The mice also have other symptoms, including a high incidence of lymphoma around 10-14 months, increased susceptibility to autoimmune diseases, and viral infections. There are no wild type control mice for this mouse strain. We have systematically phenotyped this model at multiple age groups. Publication

  

Dysferlin-deficient mice (Bla/J)A/J inbred strain is introgressed into the BL6 genetic background to generate Bla/J mice. Histological changes (centronucleated fibers and inflammation) in certain muscle (e.g., psoas, quadriceps etc) are evident around two months age and functional deficits between 4-6 months age. These mice are homozygous, and no genotyping is needed. C57BL/6 mice are the wild-type controls for this model. We have systematically phenotyped this model at multiple age groups. 

 

B6.WK-Lama2dy-2J/J (Dy2J): Mutation in laminin alpha2 gene results in progressive weakness and paralysis starting at around 14 weeks of age. The hindlimbs are affected first, and later the axial and forelimb musculature. Death usually occurs before 24 weeks of age. Skeletal muscle shows degenerative changes with proliferation of sarcolemmal nuclei, an increased amount of interstitial tissue, and size variation among individual muscle fibers. C57BL/6 mice are the wild-type controls for this model. We have systematically phenotyped this model at multiple age groups. Publication 

 

Limb girdle muscular dystrophy (LGMD) 2A mouse model

 

Calpain 3-deficient (CLPN3 -/-) mice: These mice have a very mild phenotype with minimal histological disease in skeletal muscles. These mice show reduced body weight, mild deficits in forelimb strength and motor coordination around 3 months age. Evidence of atrophy, fiber area variability, necrosis and regeneration typical of LGMD2A biopsies are seen in this model. C57BL/6 mice are the wild-type controls for this model.

 

Myositis mouse model

   

Myositis mouse model: TRE-H2Kb x CKM-tTA (HT mice): Crossbreeding TRE-H2Kb and CRE-tTA produces the mouse model of myositis (the HT mouse model), which can result in muscle weakness in the mice. The onset of disease can be controlled by administering doxycycline (0.2g/L) in the drinking water of the animals. Muscle weakness is readily apparent in female mice by 3 months of age, while males show fewer signs of disease onset. Signs of the disease onset include muscle weakness and reduced locomotor activity. Publication

 

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