Plp1 dup mice carry a tandem head-to-tail duplication of a 260.8 kb region on the X Chromosome that includes Plp1. The duplication is associated with the hyomylelinating leukodystrophy, Pelizaeus-Merzbacher disease (PMD); carrier mice exhibit progressive gait abnormalities and a progressive loss of myelin.
Grace M. Hobson, University of Delaware-A.I. duPont Hospital for Children
This strain carries a tandem head-to-tail duplication of a 260.8 kb region on the X Chromosome that includes Plp1, Tceal3, Tceal1, Morf4l2, BC065397 and Glra4. The duplication resembles duplications found in patients with Pelizaeus-Merzbacher disease (PMD).
PMD is a hyomylelinating leukodystrophy associated with mutations in PLP1 (proteolipid protein 1). Beginning at 6 months of age Plp1 dup mice develop progressive gait abnormalities characterized by decreased performance in stand index, cadence, diagonal support, three-paw support and base of support. Mice become slow moving and flat-footed. Hind limbs are more affected than forelimbs.
A progressive loss of myelin followed by axonal loss is observed in corpus callosum at 6 months of age. In the spinal cord, degenerating fibers, large vacuoles and astrogliosis are present in gray matter and to a lesser extent in white matter.
In the first targeting step Micer clone MHP312j24 was inserted proximal to Plp1. The construct was electroporated into 129S7/SvEvBrd-derived AB2.2 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. Chimeric males were crossed to C57BL/6J and clone 5H12 was selected for the second round of targeting. Micer clone MHPP264b06 was inserted distal to Plp1 and electroporated into cells from clone 5H12. Positive clone 1C7 was transfected with a Cre recombinase expressing plasmid to remove loxP sites from the 5’ and 3’ regions of the HPRT gene that was inserted with the genomic clones. Recombination between the loxP sites generates the 260.8 kb duplication that includes Plp1, Tceal3, Tceal1, Morf4l2, BC065397 and Glra4 and a functional Hprt gene. Selection was performed with HAT media and clones exhibiting the expected pattern were injected into blastocysts. Chimeric males were crossed to C57BL/6J and offspring were backcrossed to C57BL/6J for 10 generations. Upon arrival, mice were bred to C57BL/6J for at least 1 generation to establish the colony.
|Allele Name||duplication, Chr X, Grace Hobson 1|
|Allele Synonym(s)||Dp(XMHPN312j24-MHPP264b06)1Tju; Dp(XTceal3-Plp1)1Tju; Plp1 dup|
|Gene Symbol and Name||Dp(XTceal3-Plp1)1Gmh, duplication 1, Grace Hobson|
|Strain of Origin||129S7/SvEvBrd-Hprtb-m2|
|Molecular Note||Micer clones MHPN312j24 (NCBIM37, 133123007-133127471) and MHPP264b06 (NCBIM37, 133374577-133383807) and cre mediated recombination were used to generate a tandem head-to-tail duplication of a 260.8 kb region between the two sites and a complete HPRT gene at the junction. The duplication spans from Tceal3 through 9.5 kb distal of Plp1. Presence of a duplication was confirmed in mice by semiquantitative multiplex PCR, Southern blot analysis, and FISH. qRT-PCR indicates an increase in Plp1, Tceal1, Tceal3, Morf4l2 and BC065397 transcript levels at multiple postnatal time points.|
The Donating Investigator maintains this strain as a heterozygous female to C57BL/6 male cross. The duplication is X-linked. Homozygous females have not been generated. The donating investigator has not used hemizygous males for breeding. Hemizygous males have light bellies and some agouti coat color due to the coat color genes carried on the targeting vectors.
When using the Plp1 dup mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #37346 in your Materials and Methods section.