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

Peter Lauffer*, Eveline Boudin, Daniëlle C.M. Van Der Kaay, Saskia Koene, Arie Van Haeringen, Vera Van Tellingen, Wim Van Hul, Timothy C.R. Prickett, Geert Mortier, Eric A. Espiner, Hermine A. Van Duyvenvoorde

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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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.

Original languageEnglish
Article numberbvac019
JournalJournal of the Endocrine Society
Issue number4
Publication statusPublished - 1 Apr 2022

Bibliographical note

Grant Numbers
T.C.R.P. received a New Zealand Heart Foundation Senior
Fellowship (grant number 1756).
E.B. received a postdoctoral grant of the research foundation Flanders (FWO Vlaanderen; grant number 12A3814N).

Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.


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