ClinVar

In affected individuals from 3 unrelated families from Egypt (family 1), Belgium (family 2), and Italy (family 3) with cardioacrofacial dysplasia (CAFD1; 619142), Palencia-Campos et al. (2020) identified heterozygosity or mosaicism for a c.409G-A transition (c.409G-A, NM_002730.4) in the PRKACA gene, resulting in a gly137-to-arg (G137R) substitution at a highly conserved residue at a tethering surface that interacts with regulatory proteins. The G137R variant was not found in the gnomAD database. In the Egyptian proband (P1), the variant was mosaic, with a variant allele fraction (VAF) of 0.28; his 2 affected offspring for whom DNA was available carried the variant in heterozygous state. The unaffected father of the Belgian proband (P2) was mosaic for G137R (VAF 0.16), but the variant was germline-transmitted in P2 (VAF 0.55) and her affected fetus (VAF 0.46). The mutation was found to have occurred de novo in the Italian proband (P3). Fluorescence polarization assays of purified holoenzymes showed greater sensitivity of the mutant holoenzyme to lower cAMP concentrations than with wildtype protein, and PepTag assay in transfected HEK293 cells showed increased kinase activity with the G137R mutant at low cAMP concentrations compared to wildtype protein. Analysis of hedgehog (see 600725) pathway signaling in retrotransduced NIH 3T3 cells after stimulation with the SMO (601500) agonist SAG revealed that the G137R mutant impairs SAG-mediated inactivation of PKA.