TY - JOUR
T1 - Broadening the Spectrum of Loss-of-Function Variants in NPR-C-Related Extreme Tall Stature
AU - Lauffer, Peter
AU - Boudin, Eveline
AU - van der Kaay, Daniëlle C. M.
AU - Koene, Saskia
AU - van Haeringen, Arie
AU - van Tellingen, Vera
AU - van Hul, Wim
AU - Prickett, Timothy C. R.
AU - Mortier, Geert
AU - Espiner, Eric A.
AU - van Duyvenvoorde, Hermine A.
N1 - Publisher Copyright: © 2022 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
AB - 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.
KW - CNP
KW - Macrodactyly
KW - NPR3
KW - Natriuretic peptide receptor-C
KW - Natriuretic peptides
KW - Tall stature
UR - http://www.scopus.com/inward/record.url?scp=85126436881&partnerID=8YFLogxK
U2 - https://doi.org/10.1210/jendso/bvac019
DO - https://doi.org/10.1210/jendso/bvac019
M3 - Article
C2 - 35233476
SN - 2472-1972
VL - 6
JO - Journal of the Endocrine Society
JF - Journal of the Endocrine Society
IS - 4
M1 - bvac019
ER -