D2.129(B6)-Ppcd1/J

Stock number: 018051

Description

This spontaneous mutation strain involves a duplication of a mouse Chromosome 2 interval that is syntenic to the human Chromosome 20 region associated with Posterior Polymorphous Corneal Dystrophy (PPCD). This strain may be useful as a model of PPCD, iridocorneal endothelial syndrome (ICE), and glaucoma.

Detailed description

Posterior Polymorphous Corneal Dystrophy (PPCD) is a dominantly inherited autosomal condition affecting the Descemet membrane and the neighboring corneal endothelium of the eye. Affected individuals show a range of outcomes varying from minimal visual impairment to severe degradation of the cornea with opacity and edema of the eye. Glaucoma and iridocorneal endothelial syndrome (ICE) may also be associated.

This spontaneous mutation occurred in R1 (129X1/SvJ x 129S1/Sv)F1- Kitl⁺-derived embryonic stem cells. It involves a duplication of a mouse Chromosome 2 interval that is syntenic to the human Chromosome 20 region associated with PPCD. The endpoints of the segment disrupt and reduce the expression of the Csrp2bp and 6330439K17Rik genes and duplicate the region corresponding to the pseudogene LOC100043552 . Hemizygous mice show an enlarged anterior chamber resulting from metaplasia of the corneal endothelium and blockage of iridocorneal angle by epithelialized corneal endothelial cells. The stratified corneal cells with abnormal patterns of cytokeratin expression are similar to those observed in the human condition. The phenotype is seen in both eyes of the animals, generally by the time the eyes open. Both males and females are equally affected. This mutation shows decreased penetrance on a C57BL/6 genetic background but full penetrance on this DBA/2J background. Homozygotes die during embryonic development. This strain may be useful as a model of PPCD, ICE and glaucoma.

Development

(129X1/SvJ x 129S1/Sv)F1- Kitl⁺-derived R1 embryonic stem cells carrying a targeted Por (also known as Cypor) mutation [Por^tm1Cbk] were introduced to C57BL/6 blastocysts. Animals were maintained on a mixed 129-C57BL/6 genetic background. Four founder males gave rise to mice that displayed an enlarged anterior chamber of their eye. Affected animals that were wildtype for the Por mutation were selected and backcrossed to DBA/2J for 20 generations by the donating laboratory.

The mice were found to carry a duplication of a mouse Chromosome 2 interval that is syntenic to the human Chromosome 20 region associated with PPCD. The endpoints of the segment disrupt and reduce the expression of the Csrp2bp and 6330439K17Rik genes and duplicate the region corresponding to the pseudogene LOC100043552.

Allele

Symbol: Ppcd1
Name: posterior polymorphous corneal dystrophy 1
MGI accession ID: MGI:4830871
Generation method: Spontaneous
Attributes: Null/Knockout
Marker symbol: Ppcd1
Marker name: posterior polymorphous corneal dystrophy 1
Chromosome: 2
Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Molecular note: A spontaneous mutation in the embryonic cell line containing Por^tm1Cbk. Although initially identified as a duplication, the mutation contains a 3.9 Mbp chromosomal inversion flanked by 81 Kbp and 542 bp deletions. The deletion encompasses the 3' ends of Kat14 (exon 8 through 11) and Dzank1 (6330439K17Rik) (exon 20 and 21) as well as all of Zfp133-ps. The distal breakpoint of the inversion is a fusion between Chr2:144479015 bp, located in Intron 19 of Dzank1, and Chr2:148326553 bp, located 68824 bp 5' of the gene Sstr4. Quantitative RT-PCR confirmed the decreased transcript expression of the genes on either extreme of the duplicated segment in eye extracts at days 16 and 28.