1. Broadening the Spectrum of Loss-of-Function Variants in NPR-C-Related Extreme Tall Stature
- Author
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Lauffer, P., Boudin, E., Kaay, D.C.M. van der, Koene, S., Haeringen, A. van, Tellingen, V. van, Hul, W. van, Prickett, T.C.R., Mortier, G., Espiner, E.A., Duyvenvoorde, H.A. van, Pediatrics, Graduate School, Paediatric Endocrinology, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Gastroenterology Endocrinology Metabolism, and Paediatrics
- Subjects
Science & Technology ,ATRIAL-NATRIURETIC-PEPTIDE ,CLEARANCE ,Endocrinology, Diabetes and Metabolism ,OVERGROWTH ,CHILDREN ,macrodactyly ,GENE ,tall stature ,TRANSLOCATION ,Endocrinology & Metabolism ,AMINO-TERMINAL PROPEPTIDE ,SDG 3 - Good Health and Well-being ,CNP ,GROWTH ,Human medicine ,natriuretic peptide receptor-C ,NPR3 ,OVEREXPRESSION ,natriuretic peptides ,Life Sciences & Biomedicine ,HETEROZYGOUS MUTATIONS - 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.
- Published
- 2022