International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 174 -  A LOSS-OF-FUNCTION MUTATION IN NATRIURETIC PEPTIDE RECEPTOR 2 (NPR2) GENE IS RESPONSIBLE FOR MOUSE ACHONDROPLASIA

Tsuji T, Kunieda T

Okayama University, Okayama, Japan

The achondroplastic (cn/cn) mouse is a spontaneous mutant found in the AKR/J colony at the Jackson Laboratory, which is characterized by an achondroplastic dwarfism with short limbs and tail due to disturbed chondrogenesis in the endochondral ossification. The cn locus has been mapped to mouse chromosome 4, but precise localization has not yet been determined. In this study, we preciously mapped the cn locus by linkage analysis and identified the causative gene for the cn/cn mutant. By linkage analysis using 115 affected mice of F2 progeny, the cn locus was mapped on a 0.8-cM region of chromosome 4. We found that Npr2 gene localized in this region was most potent candidate gene. The sequence analysis of the gene revealed a T to G transversion leading to an amino acid substitution of highly conserved Leu to Arg in the guanylyl cyclase catalytic domain of NPR2. Npr2 gene encodes a receptor for C-type natriuretic peptide (CNP), which positively regulates longitudinal bone growth by intracellular cGMP production. No significant increase of intracellular cGMP level in response to CNP stimulus was observed in the chondrocytes of the cn/cn mice, while it was evident in the chondrocyte of the wild-type mice. Similar results were also obtained by transfection of mutant or wild-type Npr2 gene in COS-7 cells. These results indicate that the achondroplasia of cn/cn mouse is caused by a loss-of-function mutation of the Npr2 gene.

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