An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature

• Published in: The journal of clinical endocrinology and metabolism Vol. 105; no. 7; pp. 2354 - 2366
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.07.2020
• Subjects: Abnormalities; Adult; Body Height - genetics; Bones; Causes of; Child; Child, Preschool; Clinical s; Computer Simulation; Female; Fingers - abnormalities; Genetic aspects; Growth disorders; Growth Disorders - genetics; Health aspects; HEK293 Cells; Humans; Limb Deformities, Congenital - genetics; Natriuretic peptides; Physiological aspects; Receptors, Atrial Natriuretic Factor - genetics; Sequence Deletion; Netherlands; macrodactyly; natriuretic peptide receptor-B; tall stature; guanylyl cyclase B; C-type natriuretic peptide; cyclic GMP
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgaa190

Abstract 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.