An activating deletion variant in the submembrane region of natriuretic peptide receptor-B causes tall stature
| Autor: | Hannes Schmidt, Hermine A van Duyvenvoorde, Franziska Werner, Eveline Boudin, Erick Miranda-Laferte, Michaela Kuhn, Peter Lauffer, Daniëlle C M van der Kaay, Arie van Haeringen, Thomas D. Mueller |
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| Přispěvatelé: | Graduate School, Paediatric Endocrinology, Amsterdam Gastroenterology Endocrinology Metabolism |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
medicine.medical_specialty Macrodactyly medicine.drug_class Endocrinology Diabetes and Metabolism Clinical Biochemistry Limb Deformities Congenital Context (language use) Biology Biochemistry tall stature Fingers chemistry.chemical_compound Exon Endocrinology cyclic GMP Internal medicine medicine Natriuretic peptide Humans Computer Simulation Child Receptor Cyclic guanosine monophosphate natriuretic peptide receptor-B guanylyl cyclase B Clinical Research Articles Growth Disorders Sequence Deletion Biochemistry (medical) macrodactyly NPR2 Body Height Endochondral bone growth HEK293 Cells chemistry Child Preschool Female Human medicine Receptors Atrial Natriuretic Factor AcademicSubjects/MED00250 C-type natriuretic peptide |
| Zdroj: | Journal of Clinical Endocrinology and Metabolism, 105(7), 2354-2366. ENDOCRINE SOC The journal of clinical endocrinology and metabolism Journal of clinical endocrinology and metabolism, 105(7), 2354-2366. The Endocrine Society The Journal of Clinical Endocrinology and Metabolism |
| ISSN: | 0021-972X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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