Context: Natriuretic peptide receptor-B (NPR-B, GC-B in rodents; gene name NPR2) is a guanylyl cyclase (GC)-coupled receptor that mediates the effect of C-type natriuretic peptide (CNP). Homozygous mutations in human NPR-B cause acromesomelic dysplasia, type Maroteaux (AMDM; OMIM 602875), an autosomal recessive skeletal dysplasia. NPR-B has an intracellular kinase homology domain (KHD), which has no kinase activity and its functional significance in vivo is currently unknown.

Objective: We examine the functional significance of a novel NPR-B KHD mutation in humans.

Patients and Methods: A 28-year-old Japanese male presented with marked short stature (118.5 cm, -9.3SD). His limbs showed marked shortening in the middle and distal segments. His parents had relatively short stature with height z-scores of -2.75 and -0.98 (his father and mother, respectively). Direct sequencing of coding region of the NPR2 gene of the family was performed. The mutant receptor activity was investigated by saturation binding assay and cGMP measurement. Additionally, interaction between the mutant and the wild type allele was investigated by the titration experiments.

Results: We identified a novel missense mutation L658F in KHD of NPR-B in homozygous and heterozygous states in the patient and his parents, respectively. The mutation conferred normal binding affinity for CNP but no discernable ligand-induced cGMP production. Furthermore, L658F mutant impaired wildtype NPR-B-mediated cGMP production in a dose-dependent manner, suggesting that short stature found in L658F heterozygote can be caused by its dominant negative effect.

Conclusions: This study provides the first evidence that intact KHD of NPR-B is essential for skeletal development.