Your browser doesn't support javascript.
loading
An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
Lauffer, Peter; Miranda-Laferte, Erick; van Duyvenvoorde, Hermine A; van Haeringen, Arie; Werner, Franziska; Boudin, Eveline; Schmidt, Hannes; Mueller, Thomas D; Kuhn, Michaela; van der Kaay, Daniëlle C M.
Afiliação
  • Lauffer P; Department of Clinical G enetics, Leiden University Medical Center, ZA Leiden, the Netherlands.
  • Miranda-Laferte E; Department of Paediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Center, AZ Amsterdam, the Netherlands.
  • van Duyvenvoorde HA; Institute of Physiology, University of Würzburg, Würzburg, Germany.
  • van Haeringen A; Department of Clinical G enetics, Leiden University Medical Center, ZA Leiden, the Netherlands.
  • Werner F; Department of Clinical G enetics, Leiden University Medical Center, ZA Leiden, the Netherlands.
  • Boudin E; Institute of Physiology, University of Würzburg, Würzburg, Germany.
  • Schmidt H; Centre of Medical Genetics, University of Antwerp, Edegem, Belgium.
  • Mueller TD; Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
  • Kuhn M; Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, Biocenter, University of Würzburg, Würzburg, Germany.
  • van der Kaay DCM; Institute of Physiology, University of Würzburg, Würzburg, Germany.
J Clin Endocrinol Metab ; 105(7)2020 07 01.
Article em En | MEDLINE | ID: mdl-32282051
CONTEXT: C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B [NPR-B], gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type). DESIGN: History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant. RESULTS: Mother's height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B. CONCLUSIONS: We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.
Assuntos
Palavras-chave

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Estatura / Deleção de Sequência / Receptores do Fator Natriurético Atrial / Transtornos do Crescimento Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Adult / Child / Child, preschool / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Estatura / Deleção de Sequência / Receptores do Fator Natriurético Atrial / Transtornos do Crescimento Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Adult / Child / Child, preschool / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article