2. Academic Validation
  3. Biallelic cGMP-dependent type II protein kinase gene ( PRKG2) variants cause a novel acromesomelic dysplasia

Biallelic cGMP-dependent type II protein kinase gene ( PRKG2) variants cause a novel acromesomelic dysplasia

  • J Med Genet. 2022 Jan;59(1):28-38. doi: 10.1136/jmedgenet-2020-107177.
Francisca Díaz-González 1 2,  Saruchi Wadhwa 3,  Maria Rodriguez-Zabala 1 4,  Somesh Kumar 5,  Miriam Aza-Carmona 1 2 4,  Lucia Sentchordi-Montané 1 2 6 7,  Milagros Alonso 8,  Istaq Ahmad 3,  Sana Zahra 3,  Deepak Kumar 3,  Neetu Kushwah 3,  Uzma Shamim 3,  Haseena Sait 5,  Seema Kapoor 5,  Belen Roldán 8,  Gen Nishimura 9,  Amaka C Offiah 10 11,  Mohammed Faruq 3,  Karen E Heath 12 2 4
Affiliations

Affiliations

  • 1 Institute of Medical and Molecular Genetics (INGEMM), IdiPAZ, Hospital Universitario La Paz, UAM, Madrid, Spain.
  • 2 Skeletal Dysplasia Multidisciplinary Unit (UMDE) and ERN-BOND, Hospital Universitario La Paz, Madrid, Spain.
  • 3 Genomics and Molecular Medicine Division, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.
  • 4 CIBERER, ISCIII, Madrid, Spain.
  • 5 Dept. of Pediatrics, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India.
  • 6 Dept. of Pediatrics, Hospital Universitario Infanta Leonor, Madrid, Spain.
  • 7 Dept. of Pediatrics, Universidad Complutense de Madrid, Madrid, Spain.
  • 8 Dept. of Pediatric Endocrinology, Hospital Universitario Ramon y Cajal, Madrid, Spain.
  • 9 Center for Intractable Disease, Saitama Medical University Hospital, Saitama, Japan.
  • 10 Academic Unit of Chlld Health, The University of Sheffield, Sheffield, UK.
  • 11 Dept. of Radiology and ERN-BOND, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.
  • 12 Institute of Medical and Molecular Genetics (INGEMM), IdiPAZ, Hospital Universitario La Paz, UAM, Madrid, Spain [email protected].
PMID: 33106379 DOI: 10.1136/jmedgenet-2020-107177
Abstract

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).

Keywords

bone diseases; endocrine; gene expression regulation; genomics; human genetics; molecular medicine.

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