Homozygotes Prg4 knockout mice develop progressive damage to articulating joints similar to that found in the human autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP).
Matthew Warman, Boston Children's Hospital, Harvard Medical School
Loss-of-function mutations in lubricin (a secreted glycoprotein encoded by the gene PRG4 (proteoglycan 4 (megakaryocyte stimulating factor, articular superficial zone protein)) cause the human autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP).
In this strain, a non-functional lacZ cassette was knocked into the mouse Prg4 gene, creating a knockout allele. Homozygotes are born at predicted Mendelian frequencies and have normal viability and fertility. Newborn mice have normal-appearing cartilage histology. At 2 months of age, the joints of homozygous mice are significantly different from those in wildtype and heterozygous animals. Synovial hyperplasia and subintimal fibrosis, proteinacious deposits on the cartilage surface, and irregular cartilage surfaces and endochondral growth plates are seen.
By 4 months of age homozygotes begin to exhibit swelling of the tarsal (ankle) joints and flexion deformity of the hind paws. Abnormal protein deposits on the cartilage surface occur and the underlying superficial zone chondrocytes disappear. Intimal cells in the synovium surrounding the joint space become hyperplastic, further contributing to joint failure. Tendon and tendon sheath involvement is present in the ankle joints, where morphologic changes and abnormal calcification of these structures is observed. Affected animals develop an abnormal hopping gate.
By 9 months of age, the knee joint space in homozygous animals becomes filled by a non-inflammatory hyperplastic synovium, and the articular cartilage surface is barely recognizable.
Exon 6 was replaced with a lacZ-neomycin resistance cassette through homologous recombination in (129X1/SvJ x 129S1/Sv)F1- Kitl+-derived R1 embryonic stem (ES) cells. The background of this strain is predominantly C57BL/6J with small amounts of 129 and unknown other genetic contributions. Although the targeted allele was intended to create a Prg4-lacZ fusion transcript, no mutant RNA species can be detected by Northern blot of liver RNA. RT-PCR studies of synovial and liver mRNA demonstrate aberrant mRNA splicing.
|Allele Name||targeted mutation 1, Matthew Warman|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Prg4, proteoglycan 4 (megakaryocyte stimulating factor, articular superficial zone protein)|
|Strain of Origin||(129X1/SvJ x 129S1/Sv)F1-Kitl+|
|Molecular Note||The targeting construct was designed to create a Prg4-B-gal fusion protein by substituting lacZ for exon 6. Northern blot and in situ hybridization, however, detected no transcript in livers of mutant mice. RT-PCR of synovial and liver mRNA showed aberrant mRNA splicing from the allele which was thought to create a nonsense mediated mRNA decay.|
Heterozygotes and homozygotes are viable and fertile.
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