Transgenic expression of the p.Val883Met mutant in chondrocytes reproduced the patients’ phenotype in mice.

<p>(<b>A</b>) Radiographs of transgenic founder No. 4 expressing the p.Val883Met mutant NPR2 with the severest phenotype (Tg. 4) and a wild-type mouse (Wt). Tg. 4 exhibited severe bone deformities including elongation of the spine with severe kyphosis, metatarsal bones and distal phalanges, and died at seven weeks of age. (<b>B</b>) The total amount of <i>Npr2</i> mRNA in costal cartilage of line No. 28 offspring (Tg. 28) and wild-type littermates (Wt) at 5 days of age. The expression of <i>Npr2</i> mRNA in Tg. 28 was 5.1 times that in Wt. Results are presented as the mean ± SD (N = 3, *<i>p</i><0.05). (<b>C</b>) Concentration of cGMP in costal cartilage of Tg. 28 and Wt at 5 days of age. The cGMP concentration in Tg. 28 was 17.3 times that in Wt. Results are presented as the mean ± SD (N = 3, *<i>p</i><0.05). (<b>D–G</b>) Radiographs of Tg. 28 with a moderate phenotype and Wt at the age of 8 weeks. Body length, defined as the distance between the incisor and the anus, was longer in Tg. 28 than Wt. Total tail length was also longer in Tg. 28. The length of spinal (E) and tail (F) vertebrae was longer in Tg. 28 as well. All the metatarsal bones and distal phalanges were longer in Tg. 28 than Wt (G, arrows), and minor clinodactyly was detected, (<b>H</b>) The tail length of Tg. 28 (red line) and Wt (blue line) from 8 to 18 weeks. Tail length was always significantly longer in Tg. 28 than Wt among both males and females. Results are presented as the mean ± SD (N = 3, *<i>p</i><0.05, ** <i>p</i><0.001). (<b>I</b>) Bone length of Tg. 28 and Wt (18 week-old males). CL, Naso-occipital length of the calvarium; FL, femoral length; TL, tibial length. Results are presented as the mean ± SD (N = 3, <i>*p<0.05</i>).