Background C-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and endochondral bone growth. In humans, biallelic variants in NPR2, encoding NPR-B, cause acromesomelic dysplasia, type Maroteaux, while heterozygous variants in NPR2 (natriuretic peptide receptor 2) and NPPC (natriuretic peptide precursor C), encoding CNP, cause milder phenotypes. In contrast, no variants in cGKII, encoded by the protein kinase cGMP-dependent type II gene (PRKG2), have been reported in humans to date, although its role in longitudinal growth has been clearly demonstrated in several animal models.
Methods Exome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional characterisation was undertaken for the identified variants.
Results Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain, alter the downstream mitogen activation protein kinase signalling pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce ERK1/2 activation in response to fibroblast growth factor 2. They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9.
Conclusion In conclusion, we have clinically and molecularly characterised a new acromesomelic dysplasia, acromesomelic dysplasia, PRKG2 type (AMDP).
- bone diseases
- gene expression regulation
- human genetics
- molecular medicine
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MF and KEH are joint senior authors.
Correction notice The article has been corrected since it was published online first. The caption of figures 2, 3 and 4 were incorrectly ordered; they have been amended.
Contributors KEH and MF established and obtained financing of the project. SKu, LS-M, MA-B, MBR-M, HS, SKo clinically diagnosed and followed up the patients. GN and ACO examined and reported the radiological data. SW, MR-Z, MA-C, IA, SZ, DK, NK, US, MF and KEH analysed genetic data. FD-G, SW, IH, MR-Z, MA-C performed functional characterisation. KEH and MF analysed the data and supervised the project. FD-G and KEH wrote the first draft of the manuscript, tables and figures. All the authors revised the manuscript and approved the final version.
Funding This work was supported in part by the following grants: SAF2017-84646-R from MINECO (to KEH), Council of Scientific & Industrial Research (CSIR), India (to MF) and Indian Council of Medical Research (to MF). FG-D was supported by an FPU studentship from the Spanish Ministry of Education.
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval Ethical approval was obtained from Hospital Universitario La Paz, Madrid, Spain, and CSIR—Institute of Genomics and Integrative Biology, New Delhi, India. All participants provided informed consent for the performed genetic studies. All the procedures were performed under the Declaration of Helsinki and relevant policies in Spain and India.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
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