title: Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature.
abstract: BACKGROUND
  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.
  
  
  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 μg/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.
authors.affiliation: MD, PhD, Faculdade de Medicina da Universidade de Sao Paulo (LIM-25), Avenida Dr Arnaldo, 455 5° Andar Sala 5340, CEP 01246-903 Sao Paulo SP, Brazil. alexj@usp.br.
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Vasques
authors.forename: Naoko
authors.initials: N
authors.lastname: Amano
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Docko
authors.forename: Mariana F A
authors.initials: MF
authors.lastname: Funari
authors.forename: Elisangela P S
authors.initials: EP
authors.lastname: Quedas
authors.forename: Mirian Y
authors.initials: MY
authors.lastname: Nishi
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
mesh_terms: D001827:Body Height / Q000235:genetics*; D002648:Child; D004392:Dwarfism / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B