Broadening the Spectrum of Loss-of-Function Variants in NPR-C-Related Extreme Tall Stature

• Published in: Journal of the Endocrine Society 2022-04, Vol.6 (4), p.bvac019
• Main Authors: Lauffer, Peter, Boudin, Eveline, van der Kaay, Daniëlle C M, Koene, Saskia, van Haeringen, Arie, van Tellingen, Vera, Van Hul, Wim, Prickett, Timothy C R, Mortier, Geert, Espiner, Eric A, van Duyvenvoorde, Hermine A
• Format: Article
• Language: English
• Subjects: Analysis; Clinical; Cyclic guanylic acid; Membrane proteins; Natriuretic peptides; Public radio
• ISSN: 2472-1972; 2472-1972
• DOI: 10.1210/jendso/bvac019

Abstract Context Natriuretic peptide receptor-C (NPR-C, encoded by NPR3) belongs to a family of cell membrane–integral proteins implicated in various physiological processes, including longitudinal bone growth. NPR-C acts as a clearance receptor of natriuretic peptides, including C-type natriuretic peptide (CNP), that stimulate the cGMP-forming guanylyl cyclase-coupled receptors NPR-A and NPR-B. Pathogenic variants in CNP, NPR2, and NPR3 may cause a tall stature phenotype associated with macrodactyly of the halluces and epiphyseal dysplasia. Objective Here we report on a boy with 2 novel biallelic inactivating variants of NPR3. Methods History and clinical characteristics were collected. Biochemical indices of natriuretic peptide clearance and in vitro cellular localization of NPR-C were studied to investigate causality of the identified variants. Results We identified 2 novel compound heterozygous NPR3 variants c.943G>A p.(Ala315Thr) and c.1294A>T p.(Ile432Phe) in a boy with tall stature and macrodactyly of the halluces. In silico analysis indicated decreased stability of NPR-C, presumably resulting in increased degradation or trafficking defects. Compared to other patients with NPR-C loss-of-function, the phenotype seemed to be milder: pseudo-epiphyses in hands and feet were absent, biochemical features were less severe, and there was some co-localization of p.(Ile432Phe) NPR-C with the cell membrane, as opposed to complete cytoplasmic retention. Conclusion With this report on a boy with tall stature and macrodactyly of the halluces we further broaden the genotypic and phenotypic spectrum of NPR-C-related tall stature.