Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature

Naoko Amano, Tokuo Mukai, Yoshiya Ito, Satoshi Narumi, Toshiaki Tanaka, Susumu Yokoya, Tsutomu Ogata, Tomonobu Hasegawa

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Context: C-type natriuretic peptide-natriuretic peptide receptor B (NPR-B) signaling is critical for endochondral ossification, which is responsible for longitudinal growth in limbs and vertebrae. Biallelic NPR2 mutations cause acromesomelic dysplasia, type Maroteaux, which is bone dysplasia characterized by severe short stature and short limbs. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth. Objective: The goal of this study was to identify and characterize NPR2 mutations among Japanese patients with short stature. Subjects and Methods: We enrolled 101 unrelated Japanese patients with short stature. NPR2 and NPPC were sequenced, and the identified variants were characterized in vitro. Results: In two subjects,weidentified two novel heterozygous NPR2 mutations (R110C and Q417E) causing a loss of C-type natriuretic peptide-dependent cGMP generation capacities and having dominant-negative effects. R110C was defective in trafficking from the endoplasmic reticulum to the Golgi apparatus. In contrast, Q417E showed clear cell surface expression. Conclusions: We identified heterozygous NPR2 mutations in 2% of Japanese patients with short stature. Our in vitro findings indicate that NPR2 mutations have a dominant negative effect, and their dominant-negative mechanisms vary corresponding to the molecular pathogenesis of the mutations.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number4
DOIs
Publication statusPublished - 2014

Fingerprint

C-Type Natriuretic Peptide
Bone
Mutation
Extremities
Developmental Bone Disease
Bone Development
Golgi Apparatus
Osteogenesis
Endoplasmic Reticulum
Spine
Growth
atrial natriuretic factor receptor B
4-nitrophenylphosphorylcholine

ASJC Scopus subject areas

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

Cite this

Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature. / Amano, Naoko; Mukai, Tokuo; Ito, Yoshiya; Narumi, Satoshi; Tanaka, Toshiaki; Yokoya, Susumu; Ogata, Tsutomu; Hasegawa, Tomonobu.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 99, No. 4, 2014.

Research output: Contribution to journalArticle

Amano, Naoko ; Mukai, Tokuo ; Ito, Yoshiya ; Narumi, Satoshi ; Tanaka, Toshiaki ; Yokoya, Susumu ; Ogata, Tsutomu ; Hasegawa, Tomonobu. / Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature. In: Journal of Clinical Endocrinology and Metabolism. 2014 ; Vol. 99, No. 4.
@article{0e17e255ef3448f6b397d04e441c87e4,
title = "Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature",
abstract = "Context: C-type natriuretic peptide-natriuretic peptide receptor B (NPR-B) signaling is critical for endochondral ossification, which is responsible for longitudinal growth in limbs and vertebrae. Biallelic NPR2 mutations cause acromesomelic dysplasia, type Maroteaux, which is bone dysplasia characterized by severe short stature and short limbs. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth. Objective: The goal of this study was to identify and characterize NPR2 mutations among Japanese patients with short stature. Subjects and Methods: We enrolled 101 unrelated Japanese patients with short stature. NPR2 and NPPC were sequenced, and the identified variants were characterized in vitro. Results: In two subjects,weidentified two novel heterozygous NPR2 mutations (R110C and Q417E) causing a loss of C-type natriuretic peptide-dependent cGMP generation capacities and having dominant-negative effects. R110C was defective in trafficking from the endoplasmic reticulum to the Golgi apparatus. In contrast, Q417E showed clear cell surface expression. Conclusions: We identified heterozygous NPR2 mutations in 2{\%} of Japanese patients with short stature. Our in vitro findings indicate that NPR2 mutations have a dominant negative effect, and their dominant-negative mechanisms vary corresponding to the molecular pathogenesis of the mutations.",
author = "Naoko Amano and Tokuo Mukai and Yoshiya Ito and Satoshi Narumi and Toshiaki Tanaka and Susumu Yokoya and Tsutomu Ogata and Tomonobu Hasegawa",
year = "2014",
doi = "10.1210/jc.2013-3525",
language = "English",
volume = "99",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "4",

}

TY - JOUR

T1 - Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature

AU - Amano, Naoko

AU - Mukai, Tokuo

AU - Ito, Yoshiya

AU - Narumi, Satoshi

AU - Tanaka, Toshiaki

AU - Yokoya, Susumu

AU - Ogata, Tsutomu

AU - Hasegawa, Tomonobu

PY - 2014

Y1 - 2014

N2 - Context: C-type natriuretic peptide-natriuretic peptide receptor B (NPR-B) signaling is critical for endochondral ossification, which is responsible for longitudinal growth in limbs and vertebrae. Biallelic NPR2 mutations cause acromesomelic dysplasia, type Maroteaux, which is bone dysplasia characterized by severe short stature and short limbs. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth. Objective: The goal of this study was to identify and characterize NPR2 mutations among Japanese patients with short stature. Subjects and Methods: We enrolled 101 unrelated Japanese patients with short stature. NPR2 and NPPC were sequenced, and the identified variants were characterized in vitro. Results: In two subjects,weidentified two novel heterozygous NPR2 mutations (R110C and Q417E) causing a loss of C-type natriuretic peptide-dependent cGMP generation capacities and having dominant-negative effects. R110C was defective in trafficking from the endoplasmic reticulum to the Golgi apparatus. In contrast, Q417E showed clear cell surface expression. Conclusions: We identified heterozygous NPR2 mutations in 2% of Japanese patients with short stature. Our in vitro findings indicate that NPR2 mutations have a dominant negative effect, and their dominant-negative mechanisms vary corresponding to the molecular pathogenesis of the mutations.

AB - Context: C-type natriuretic peptide-natriuretic peptide receptor B (NPR-B) signaling is critical for endochondral ossification, which is responsible for longitudinal growth in limbs and vertebrae. Biallelic NPR2 mutations cause acromesomelic dysplasia, type Maroteaux, which is bone dysplasia characterized by severe short stature and short limbs. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth. Objective: The goal of this study was to identify and characterize NPR2 mutations among Japanese patients with short stature. Subjects and Methods: We enrolled 101 unrelated Japanese patients with short stature. NPR2 and NPPC were sequenced, and the identified variants were characterized in vitro. Results: In two subjects,weidentified two novel heterozygous NPR2 mutations (R110C and Q417E) causing a loss of C-type natriuretic peptide-dependent cGMP generation capacities and having dominant-negative effects. R110C was defective in trafficking from the endoplasmic reticulum to the Golgi apparatus. In contrast, Q417E showed clear cell surface expression. Conclusions: We identified heterozygous NPR2 mutations in 2% of Japanese patients with short stature. Our in vitro findings indicate that NPR2 mutations have a dominant negative effect, and their dominant-negative mechanisms vary corresponding to the molecular pathogenesis of the mutations.

UR - http://www.scopus.com/inward/record.url?scp=84898407176&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84898407176&partnerID=8YFLogxK

U2 - 10.1210/jc.2013-3525

DO - 10.1210/jc.2013-3525

M3 - Article

VL - 99

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 4

ER -