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

研究成果: Article査読

42 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)E713-E718
ジャーナルJournal of Clinical Endocrinology and Metabolism
99
4
DOI
出版ステータスPublished - 2014 4月

ASJC Scopus subject areas

  • 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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