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. 2022 Oct;59(10):947-950.
doi: 10.1136/jmedgenet-2021-108027. Epub 2021 Nov 15.

Variable skeletal phenotypes associated with biallelic variants in PRKG2

Alistair T Pagnamenta  1   2 , Francisca Diaz-Gonzalez  3 , Benito Banos-Pinero  4 , Matteo P Ferla  1   2 , Mehran B Toosi  5 , Alistair D Calder  6 , Ehsan G Karimiani  7   8 , Mohammad Doosti  8 , Andrew Wainwright  9 , Paul Wordsworth  1   2   9 , Kathryn Bailey  9 , Katarina Ejeskär  10 , Tracy Lester  4 , Reza Maroofian  11 , Karen E Heath  3   12 , Homa Tajsharghi  10 , Deborah Shears  13 , Jenny C Taylor  14   2 ; Genomics England Research Consortium
Collaborators, Affiliations

Variable skeletal phenotypes associated with biallelic variants in PRKG2

Alistair T Pagnamenta et al. J Med Genet. 2022 Oct.
No abstract available

Keywords: codon; frameshift mutation; genomics; musculoskeletal diseases; nonsense; phenotype.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Pedigrees, structural modelling and the effects of the PRKG2 variants on cGKII protein levels/MAPK pathway regulation. (A) Simplified pedigrees and segregation of variants in PRKG2 and COL1A1 in two families with rare skeletal dysplasias. More detailed pedigrees are shown in online supplemental figure 4. AMD, acromesomelic dysplasia (mild); ND, not determined; OI, osteogenesis imperfecta; SMD, spondylometaphyseal dysplasia; WT, wild-type; *, WGS performed as part of 100KGP; +, exome sequencing. The COL1A1 variant was initially detected by targeted sequencing in 2011 but confirmed to have arisen de novo by WGS. (B) Structure of cGKII (wild type: turquoise) with overlay of the mutant, p.Asp761Glufs*34 (salmon) extension and inset of Phe762 residue. The protein kinase domain is regulated by two cyclic nucleotides binding (CNB) domains. The predicted C-terminal extension would fall between CNB-A domain and the protein kinase domain and is likely to interfere with the activation of the latter by the former, were it to be stable, a conclusion not supported by in silico predictions. In fact, the extension results in a deleterious amino acid change of a core residue, Phe762, to a leucine (inset). Also visible is the hydrogen bond between the terminal carboxylate and Thr519, whereas the amide bond between Leu762 and Leu763 is forced away in order to best accommodate the subsequent residues. (C) Immunoblotting results for cGKII (upper panel) and GAPDH as an endogenous control (lower panel) of cell lysates extracted from transiently transfected HEK293T cells. Both human cGKII mutants as well as wild-type (WT) proteins were detected at their predicted size: R569*: 65.1 kDa and D761Efs*34: 91.1 kDa (calculated by using the ExPaSy online tool, https://web.expasy.org). (D) Densitometry quantification of cGKII showing that there is an 80% reduction in expression of the two mutants compared with WT. (E) Western blots of phosphorylated Raf-1 and ERK1/2 proteins of the MAPK pathway showed that neither of the mutants were able to phosphorylate c-Raf at Ser43 and therefore downregulate ERK activation compared with WT in response to FGF2 induction in transiently transfected HEKT293 cells. (F) Densitometry quantification of pMAPK 44/42 protein revealed that neither R569* nor D761Efs*34 mutants were able to downregulate FGF2-induced ERK1/2 activation compared with WT, in transiently transfected HEK293 cells in the presence of 8-pCPT-cGMP. Three biological experiments were performed, and significance values are represented as *p<0.05, **p<0.01, ***p<0.001 and ****p>0.0001. EV, empty vector; T−, untransfected cells.
Figure 2
Figure 2
Radiographic findings in two families with PRKG2 variants: radiographs of left upper limb (A) and lower limb (B) in a 26-month-old boy (F1-IV-7) from family 1. The long bones are stocky in appearance but there is no disproportion within the limbs. (C) Pelvic radiograph at age 4 in same child shows development of long, slender femoral necks. (D) Lateral spinal radiograph at age 4 show generalised mild platyspondyly with small central anterior projections of the vertebral bodies, and hypoplasia of the L2 vertebral body. (E) Left hand radiograph at age 11 in same child shows no brachydactyly; there is mild metaphyseal chondrodysplasia evident in the distal radius and particularly the ulna, with some metaphyseal striations (black arrow); subtle coning of the distal phalangeal metaphyses is evident (white arrows), without associated shortening. Pelvic (F) and lateral spine (G) radiographs in middle affected sibling (F1-IV-6) in family 1 showing similar features of long slender femoral necks and platyspondyly with anterior vertebral body projections. Osteopaenia is also evident; this child also has type 1 osteogenesis imperfecta due to a de novo pathogenic variant in COL1A1. Additional radiology is available for F1-IV-3 in online supplemental figure 5 which shows similar results to those for F1-IV-7. (H) Left hand radiograph in female child (F2-V-3, aged 10 years) from family 2 showing generalised brachydactyly. (I) Right upper limb radiograph also from F2-V-3 demonstrates mild disproportionate shortening of the radius and ulna relative to the humerus (mesomelic shortening). (J) Pelvic radiograph from F2-V-3 demonstrates mildly elongated femoral necks. (K) Lateral spine radiograph from the same individual demonstrates mild platyspondyly with small anterior vertebral body projections.
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