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Intact Kinase Homology Domain of Natriuretic Peptide Receptor-B Is Essential for Skeletal Development

Department of Pediatrics (R.H., T.H.), Keio University School of Medicine, 160-8582 Tokyo, Japan; Department of Molecular Medicine and Metabolism, Medical Research Institute (R.H., Y.K., T.S., Y.Og.), and Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone (Y.Og.), Tokyo Medical and Dental University, 101-0062 Tokyo, Japan; Divisions of Medical Genetics (Y.Oh., H.O.) and Metabolism and Endocrinology (H.M.), and Department of Clinical Laboratory (N.M.), Saitama Children’s Medical Center, 339-8551 Saitama, Japan; Department of Surgery (M.Sai., M.Sak.), Saitama Cardiovascular and Respiratory Center, 360-0105 Saitama, Japan; and Department of Radiology (G.N.), Tokyo Metropolitan Kiyose Children’s Hospital, 204-8567 Tokyo, Japan

Address all correspondence and requests for reprints to: Yoshihiro Ogawa, Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. E-mail: ogawa.mmm{at}mri.tmd.ac.jp.

Context: Natriuretic peptide receptor-B (NPR-B, GC-B in rodents; gene name NPR2) is a guanylyl cyclase-coupled receptor that mediates the effect of C-type natriuretic peptide. Homozygous mutations in human NPR-B cause acromesomelic dysplasia, type Maroteaux (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 examined the functional significance of a novel NPR-B KHD mutation in humans.

Patients and Methods: A 28-yr-old Japanese male presented with marked short stature (118.5 cm, –9.3 SD). 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 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 C-type natriuretic peptide but no discernible ligand-induced cGMP production. Furthermore, L658F mutant impaired wild-type 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.

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