Heterozygous Mutations in Natriuretic Peptide Receptor-B (NPR2) Gene as a Cause of Short Stature in Patients Initially Classified as Idiopathic Short Stature

Author(s)

Vasques, Gabriela A. ^{[1, 2]} ; Amano, Naoko ^[3] ; Docko, Ana J. ^[1] ; Funari, Mariana F. A. ^[2] ; Quedas, Elisangela P. S. ^[1] ; Nishi, Mirian Y. ^[2] ; Arnhold, Ivo J. P. ^[2] ; Hasegawa, Tomonobu ^[3] ; Jorge, Alexander A. L. ^[1]

Affiliation

^[1] Univ Sao Paulo, Unidade Endocrinol Genet, Lab Endocrinol Celular & Mol LIM 25, Disciplina Endocrinol, Hosp Clin, Fac Med, BR-01246903 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Unidade Endocrinol Desenvolvimento, Lab Hormonios & Genet Mol LIM 42, Hosp Clin, Disciplina Endocrinol, Fac Med, BR-05403900 Sao Paulo - Brazil

^[3] Keio Univ, Sch Med, Dept Pediat, Tokyo 1608582 - Japan

• Document type: Journal article
• Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 98, n. 10, p. E1636-E1644, OCT 2013.
• Web of Science Citations: 46

Abstract

Context: Based on the stature observed in relatives of patients with acromesomelic dysplasia, type Maroteaux, homozygous for mutations in natriuretic peptide receptor B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some children with idiopathic short stature (ISS). Objective: The objective of the study was to investigate the presence of NPR2 mutations in a group of patients with ISS. Patients and Methods: The NPR2 coding region was directly sequenced in 47 independent patients with ISS. The functional consequences of NPR2 nonsynonymous variations were established using in vitro cell-based assays. Results: Three novel heterozygous NPR2 mutations were identified: c.226T>C (p.Ser76Pro), c.788G>C (p.Arg263Pro), and c.2455C>T (p.Arg819Cys). These allelic variants were not found in our controls or in the 1000 Genomes database. In silico analysis suggested that the three missense mutations are probably damaging. All of them were selected for in vitro functional evaluation. Cells transfected with the three mutants failed to produce cyclic GMP after treatment with C-type natriuretic peptide. Cells cotransfected with mutant and wild-type-NPR-B (1:1) showed a significant decrease in cGMP levels after C-type natriuretic peptide stimulation in comparison with cells cotrasnfected with empty vector and wild type, suggesting a dominant-negative effect. These three mutations segregated with short stature phenotype in an autosomal dominant pattern (height SD score ranged from -4.5 to -1.7). One of these patients and two relatives have disproportionate short stature, whereas in another patient a nonspecific skeletal abnormality was observed. All three of these patients were treated with recombinant human GH (33-50 mu g/kg.d) without significant height SD score change during therapy. Conclusions: We identified heterozygous NPR2 mutations in 6% of patients initially classified as ISS. Affected patients have mild and variable degrees of short stature without a distinct phenotype. Heterozygous mutations in NPR2 could be an important cause of nonsyndromic familial short stature. (AU)

• FAPESP's process: 11/11801-9 - Search for mutations in C-type natriuretic peptide receptor gene (NPR2) in individuals with idiopathic short stature
• Grantee: Gabriela de Andrade Vasques
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Research Projects - Thematic Grants