Mutations in C-natriuretic Peptide (NPPC): a Novel Cause of Autosomal Dominant Short Stature

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2017 Jun 30

PMID 28661490

Citations 31

Authors

Alfonso Hisado-Oliva

Alba Ruzafa-Martin

Lucia Sentchordi

Mariana F A Funari

Carolina Bezanilla-Lopez

Marta Alonso-Bernaldez

Jimena Barraza-Garcia

Maria Rodriguez-Zabala

Antonio M Lerario

Sara Benito-Sanz

Miriam Aza-Carmona

Angel Campos-Barros

Alexander A L Jorge

Karen E Heath

Affiliations

Soon will be listed here.

Abstract

PurposeC-type natriuretic peptide (CNP) and its principal receptor, natriuretic peptide receptor B (NPR-B), have been shown to be important in skeletal development. CNP and NPR-B are encoded by natriuretic peptide precursor-C (NPPC) and natriuretic peptide receptor 2 (NPR2) genes, respectively. While NPR2 mutations have been described in patients with skeletal dysplasias and idiopathic short stature (ISS), and several Npr2 and Nppc skeletal dysplasia mouse models exist, no mutations in NPPC have been described in patients to date.MethodsNPPC was screened in 668 patients (357 with disproportionate short stature and 311 with autosomal dominant ISS) and 29 additional ISS families in an ongoing whole-exome sequencing study.ResultsTwo heterozygous NPPC mutations, located in the highly conserved CNP ring, were identified. Both showed significant reductions in cyclic guanosine monophosphate synthesis, confirming their pathogenicity. Interestingly, one has been previously linked to skeletal abnormalities in the spontaneous Nppc mouse long-bone abnormality (lbab) mutant.ConclusionsOur results demonstrate, for the first time, that NPPC mutations cause autosomal dominant short stature in humans. The NPPC mutations cosegregated with a short stature and small hands phenotype. A CNP analog, which is currently in clinical trials for the treatment of achondroplasia, seems a promising therapeutic approach, since it directly replaces the defective protein.

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References

Vasques G, Amano N, Docko A, Funari M, Quedas E, Nishi M . Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature. J Clin Endocrinol Metab. 2013; 98(10):E1636-44. DOI: 10.1210/jc.2013-2142. View

Wendt D, Dvorak-Ewell M, Bullens S, Lorget F, Bell S, Peng J . Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J Pharmacol Exp Ther. 2015; 353(1):132-49. DOI: 10.1124/jpet.114.218560. View

Wu C, Wu F, Pan J, Morser J, Wu Q . Furin-mediated processing of Pro-C-type natriuretic peptide. J Biol Chem. 2003; 278(28):25847-52. DOI: 10.1074/jbc.M301223200. View

Gudbjartsson D, Walters G, Thorleifsson G, Stefansson H, Halldorsson B, Zusmanovich P . Many sequence variants affecting diversity of adult human height. Nat Genet. 2008; 40(5):609-15. DOI: 10.1038/ng.122. View

Bartels C, Bukulmez H, Padayatti P, Rhee D, van Ravenswaaij-Arts C, Pauli R . Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet. 2004; 75(1):27-34. PMC: 1182004. DOI: 10.1086/422013. View

Tassano E, Buttgereit J, Bader M, Lerone M, Divizia M, Bocciardi R . Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations. PLoS One. 2013; 8(6):e66048. PMC: 3689787. DOI: 10.1371/journal.pone.0066048. View

Krejci P, Masri B, Fontaine V, Mekikian P, Weis M, Prats H . Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis. J Cell Sci. 2005; 118(Pt 21):5089-100. DOI: 10.1242/jcs.02618. View

Tsuji T, Kondo E, Yasoda A, Inamoto M, Kiyosu C, Nakao K . Hypomorphic mutation in mouse Nppc gene causes retarded bone growth due to impaired endochondral ossification. Biochem Biophys Res Commun. 2008; 376(1):186-90. DOI: 10.1016/j.bbrc.2008.08.139. View

Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T . Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet. 2012; 91(6):1108-14. PMC: 3516592. DOI: 10.1016/j.ajhg.2012.10.014. View

10.

Potter L, Abbey-Hosch S, Dickey D . Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2005; 27(1):47-72. DOI: 10.1210/er.2005-0014. View

11.

Tamura N, Doolittle L, Hammer R, Shelton J, Richardson J, Garbers D . Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs. Proc Natl Acad Sci U S A. 2004; 101(49):17300-5. PMC: 534612. DOI: 10.1073/pnas.0407894101. View

12.

Jiao Y, Yan J, Jiao F, Yang H, Donahue L, Li X . A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice. BMC Genet. 2007; 8:16. PMC: 1867825. DOI: 10.1186/1471-2156-8-16. View

13.

Yoder A, Kruse A, Earhart C, Ohlendorf D, Potter L . Reduced ability of C-type natriuretic peptide (CNP) to activate natriuretic peptide receptor B (NPR-B) causes dwarfism in lbab -/- mice. Peptides. 2008; 29(9):1575-81. PMC: 4429774. DOI: 10.1016/j.peptides.2008.04.020. View

14.

Wood A, Esko T, Yang J, Vedantam S, Pers T, Gustafsson S . Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet. 2014; 46(11):1173-86. PMC: 4250049. DOI: 10.1038/ng.3097. View

15.

Chusho H, Tamura N, Ogawa Y, Yasoda A, Suda M, Miyazawa T . Dwarfism and early death in mice lacking C-type natriuretic peptide. Proc Natl Acad Sci U S A. 2001; 98(7):4016-21. PMC: 31171. DOI: 10.1073/pnas.071389098. View

16.

Wang S, Jacobsen C, Carmichael H, Edmund A, Robinson J, Olney R . Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature. Hum Mutat. 2015; 36(4):474-81. PMC: 4382411. DOI: 10.1002/humu.22773. View

17.

Kake T, Kitamura H, Adachi Y, Yoshioka T, Watanabe T, Matsushita H . Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice. Am J Physiol Endocrinol Metab. 2009; 297(6):E1339-48. DOI: 10.1152/ajpendo.00272.2009. View

18.

Ozasa A, Komatsu Y, Yasoda A, Miura M, Sakuma Y, Nakatsuru Y . Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells. Bone. 2005; 36(6):1056-64. DOI: 10.1016/j.bone.2005.03.006. View

19.

Estrada K, Krawczak M, Schreiber S, van Duijn K, Stolk L, van Meurs J . A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation. Hum Mol Genet. 2009; 18(18):3516-24. PMC: 2729669. DOI: 10.1093/hmg/ddp296. View

20.

Tsuji T, Kunieda T . A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse. J Biol Chem. 2005; 280(14):14288-92. DOI: 10.1074/jbc.C500024200. View