Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development

Rumi Hachiya, Yuko Ohashi, Yasutomi Kamei, Takayoshi Suganami, Hiroshi Mochizuki, Norimasa Mitsui, Masaaki Saitoh, Masako Sakuragi, Gen Nishimura, Hirofumi Ohashi, Tomonobu Hasegawa, Yoshihiro Ogawa

研究成果: ジャーナルへの寄稿学術誌査読

51 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)4009-4014
ページ数6
ジャーナルJournal of Clinical Endocrinology and Metabolism
92
10
DOI
出版ステータス出版済み - 10月 2007
外部発表はい

!!!All Science Journal Classification (ASJC) codes

  • 内分泌学、糖尿病および代謝内科学
  • 生化学
  • 内分泌学
  • 臨床生化学
  • 生化学、医学

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