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

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Abstract

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.

Original languageEnglish
Pages (from-to)4009-4014
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number10
DOIs
Publication statusPublished - Oct 2007

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Phosphotransferases
C-Type Natriuretic Peptide
Mutation
Guanylate Cyclase-Coupled Receptors
Genes
Parents
Genetic Databases
Guanylate Cyclase
Missense Mutation
Heterozygote
Titration
Fathers
Names
Rodentia
Assays
Extremities
Alleles
Mothers
atrial natriuretic factor receptor B
Ligands

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development. / Hachiya, Rumi; Ohashi, Yuko; Kamei, Yasutomi; Suganami, Takayoshi; Mochizuki, Hiroshi; Mitsui, Norimasa; Saitoh, Masaaki; Sakuragi, Masako; Nishimura, Gen; Ohashi, Hirofumi; Hasegawa, Tomonobu; Ogawa, Yoshihiro.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 92, No. 10, 10.2007, p. 4009-4014.

Research output: Contribution to journalArticle

Hachiya, R, Ohashi, Y, Kamei, Y, Suganami, T, Mochizuki, H, Mitsui, N, Saitoh, M, Sakuragi, M, Nishimura, G, Ohashi, H, Hasegawa, T & Ogawa, Y 2007, 'Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development', Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 10, pp. 4009-4014. https://doi.org/10.1210/jc.2007-1101
Hachiya, Rumi ; Ohashi, Yuko ; Kamei, Yasutomi ; Suganami, Takayoshi ; Mochizuki, Hiroshi ; Mitsui, Norimasa ; Saitoh, Masaaki ; Sakuragi, Masako ; Nishimura, Gen ; Ohashi, Hirofumi ; Hasegawa, Tomonobu ; Ogawa, Yoshihiro. / Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development. In: Journal of Clinical Endocrinology and Metabolism. 2007 ; Vol. 92, No. 10. pp. 4009-4014.
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abstract = "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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AU - Ohashi, Yuko

AU - Kamei, Yasutomi

AU - Suganami, Takayoshi

AU - Mochizuki, Hiroshi

AU - Mitsui, Norimasa

AU - Saitoh, Masaaki

AU - Sakuragi, Masako

AU - Nishimura, Gen

AU - Ohashi, Hirofumi

AU - Hasegawa, Tomonobu

AU - Ogawa, Yoshihiro

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N2 - 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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