B10.Cg-Cmah^tm1Avrk Dmd^mdx/PtmJ

Stock number: 017929
Product name: B10.Cmah-mdx
Research areas: Cell Biology Research, Developmental Biology Research, Mouse/Human Gene Homologs, Neurobiology Research, Sensorineural Research

Description

Cmah-mdx mice are useful for studying how human-like CMAH-deficiency accelerates the onset and severity of the Duchenne muscular dystrophy (DMD) seen in Dmd^mdx mice. Cmah-mdx mice better mimic the human disease than the current standard model, and thus provide a model for DMD where translational research will be more relevant to issues affecting humans with the disease.

Detailed description

These Cmah-mdx mutant mice harbor two mutations; the Cmah knockout allele (Cmah^tm1Avrk) and the spontaneous X-linked muscular dystrophy mutation (Dmd^mdx). The Cmah knockout allele abolishes Cmah expression; eliminating biosynthesis of N-glycolylneuraminic acid (Neu5Gc) from all cells and mimicking the normal human lack of functional CMAH. The Dmd^mdx mutation abolishes dystrophin expression and models Duchenne muscular dystrophy (DMD) with less severe myopathology.

Compared to homozygous mdx mice (Dmd^mdx/mdx females / Dmd^mdx/Y males), Cmah-deficiency in homozygous Cmah-mdx mice (Cmah^-/-;Dmd^mdx/mdx females / Cmah^-/-;Dmd^mdx/Y males) results in accelerated age of onset, rate of progression, and severity of the major DMD phenotypes contributing to morbidity and mortality. This is especially true for loss of ambulation, cardiac and respiratory muscle weakness, and loss of lifespan. Homozygous Cmah-mdx mice also exhibit diminished expression/function of the dystrophin-associated glycoprotein (DAG) complex and increased activation of complement. Specifically, homozygous Cmah-mdx mice have Neu5Gc accumulation into small regenerating muscles in dystrophic regions. Some homozygous Cmah-mdx mice exhibit serum antibodies to Neu5Gc and increased classical complement Neu5Gc-dependent killing of muscle cells. The donating investigator reports one can successfully breed Cmah^-/-;Dmd^mdx/mdx females with Cmah^-/-;Dmd^mdx/Y males if the mice are young (starting at 6-8 weeks old).

Heterozygous Cmah-mdx mice (Cmah^+/-;Dmd^mdx/mdx females / Cmah^+/-;Dmd^mdx/Y males) are viable and fertile. The donating investigator reports heterozygous Cmah-mdx mice exhibit the same phenotypic traits as homozygous mdx mice (Dmd^mdx/mdx females / Dmd^mdx/Y males).

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for these mice. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available. To view the phenotype describing the Cmah knockout mice a C57BL/6 genetic background, please see Stock No. 017588. To view the phenotype describing the mdx mutant mice on a C57BL/10ScSn genetic background, please see Stock No. 001801.

Development

These Cmah-mdx mutant mice harbor two mutations; the Cmah knockout allele (Cmah^tm1Avrk) and the spontaneous X-linked muscular dystrophy mutation (Dmd^mdx).

The Cmah knockout allele was designed by Dr. Ajit Varki (University of California San Diego) to have human-like inactivation of CMAH function via deletion of exon 6. Mice harboring the Cmah knockout allele (on a C57BL/6 congenic background) are described and available from The Jackson Laboratory Repository as Stock No. 017588.

C57BL/10ScSn mice harboring the spontaneous X-linked muscular dystrophy mdx allele are described and available from The Jackson Laboratory Repository as Stock No. 001801.

To generate this Cmah-mdx mutant line, Dr. Paul T. Martin (The Research Institute at Nationwide Children's Hospital, Columbus Ohio) bred C57BL/6 congenic Cmah^-/- males with C57Bl/10ScSn-Dmd^mdx/mdx females. The resulting male offspring (F1; Cmah^+/-;Dmd^mdx/Y) were bred with C57Bl/10ScSn-Dmd^mdx/mdx females to create F2 generation mice that were all dystrophin-deficient. The Cmah-mdx colony was then maintained by breeding Cmah^+/-;Dmd^mdx/Y males with C57Bl/10ScSn-Dmd^mdx/mdx females for more than ten generations. The Cmah-mdx colony was then maintained by breeding Cmah^-/-;Dmd^mdx/mdx females with Cmah^-/-;Dmd^mdx/Y males prior to sending to The Jackson Laboratory Repository. Upon arrival, mice were bred with C57BL/10ScSnJ inbred mice (Stock No. 000476) for at least one generation to establish The Jackson Laboratory Repository colony.

Allele

Symbol: Dmd^mdx
Name: X linked muscular dystrophy
MGI accession ID: MGI:1856328
Generation method: Spontaneous
Synonyms: pke; mdx; pyruvate kinase expression
Marker symbol: Dmd
Marker name: dystrophin, muscular dystrophy
Chromosome: X
Strain of origin: C57BL/10ScSn
Molecular note: This mutation arose in 1981 in a C57BL/10ScSn colony at University of Leicester. A C-to-T substitution in the CAA codon in exon 23 (ENSMUST00000114000 chrX:g.83803333C>T; c.2983C>T; p.Q995*) results in a termination codon (TAA) in place of a glutamine codon. This allele is predicted to produce a truncated protein.

Allele

Symbol: Cmah^tm1Avrk
Name: targeted mutation 1, Ajit Varki
MGI accession ID: MGI:3715527
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: Cmah^-
Marker symbol: Cmah
Marker name: cytidine monophospho-N-acetylneuraminic acid hydroxylase
Chromosome: 13
Strain of origin: 129X1/SvJ
Molecular note: Exon 6 and a floxed TK/neo were removed via transient cre mediated recombination.