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

Overview

Journal J Endocr Soc

Specialty Endocrinology

Date 2022 Mar 2

PMID 35233476

Authors

Peter Lauffer

Eveline Boudin

Danielle 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

Affiliations

Soon will be listed here.

Abstract

Context: Natriuretic peptide receptor-C (NPR-C, encoded by ) 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 , , and 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 .

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 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.

Citing Articles

Comprehensive genetic testing approaches as the basis for personalized management of growth disturbances: current status and perspectives.

van der Kaay D, Rochtus A, Binder G, Kurth I, Prawitt D, Netchine I Endocr Connect. 2022; 11(11).

PMID: 36064195 PMC: 9578069. DOI: 10.1530/EC-22-0277.

Lui J, Baron J J Endocr Soc. 2022; 6(6):bvac064.

PMID: 35528827 PMC: 9070793. DOI: 10.1210/jendso/bvac064.

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

Lauffer P, Boudin E, van der Kaay D, Koene S, van Haeringen A, van Tellingen V J Endocr Soc. 2022; 6(4):bvac019.

PMID: 35233476 PMC: 8879884. DOI: 10.1210/jendso/bvac019.

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