RT Journal Article SR Electronic T1 Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 28 OP 38 DO 10.1136/jmedgenet-2020-107177 VO 59 IS 1 A1 Díaz-González, Francisca A1 Wadhwa, Saruchi A1 Rodriguez-Zabala, Maria A1 Kumar, Somesh A1 Aza-Carmona, Miriam A1 Sentchordi-Montané, Lucia A1 Alonso, Milagros A1 Ahmad, Istaq A1 Zahra, Sana A1 Kumar, Deepak A1 Kushwah, Neetu A1 Shamim, Uzma A1 Sait, Haseena A1 Kapoor, Seema A1 Roldán, Belen A1 Nishimura, Gen A1 Offiah, Amaka C A1 Faruq, Mohammed A1 Heath, Karen E. YR 2022 UL http://jmg.bmj.com/content/59/1/28.abstract AB 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).Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.