Scientific article
Case report
Open access

Pediatric encephalopathy: cinical, biochemical and cellular insights into the role of Gln52 of GNAO1 and GNAI1 for the dominant disease

Published inCells, vol. 10, no. 10, 2749
Publication date2021-10-14
First online date2021-10-14

Heterotrimeric G proteins are immediate transducers of G protein-coupled receptors—the biggest receptor family in metazoans—and play innumerate functions in health and disease. A set of de novo point mutations in GNAO1 and GNAI1, the genes encoding the α-subunits (Gαo and Gαi1, respectively) of the heterotrimeric G proteins, have been described to cause pediatric encephalopathies represented by epileptic seizures, movement disorders, developmental delay, intellectual disability, and signs of neurodegeneration. Among such mutations, the Gln52Pro substitutions have been previously identified in GNAO1 and GNAI1. Here, we describe the case of an infant with another mutation in the same site, Gln52Arg. The patient manifested epileptic and movement disorders and a developmental delay, at the onset of 1.5 weeks after birth. We have analyzed biochemical and cellular properties of the three types of dominant pathogenic mutants in the Gln52 position described so far: Gαo[Gln52Pro], Gαi1[Gln52Pro], and the novel Gαo[Gln52Arg]. At the biochemical level, the three mutant proteins are deficient in binding and hydrolyzing GTP, which is the fundamental function of the healthy G proteins. At the cellular level, the mutants are defective in the interaction with partner proteins recognizing either the GDP-loaded or the GTP-loaded forms of Gαo. Further, of the two intracellular sites of Gαo localization, plasma membrane and Golgi, the former is strongly reduced for the mutant proteins. We conclude that the point mutations at Gln52 inactivate the Gαo and Gαi1 proteins leading to aberrant intracellular localization and partner protein interactions. These features likely lie at the core of the molecular etiology of pediatric encephalopathies associated with the codon 52 mutations in GNAO1/GNAI1.

  • G proteins
  • GNAI1
  • GNAO1
  • GTP binding
  • Gln52
  • Golgi
  • Case report
  • Dominant mutation
  • Molecular etiology
  • Pediatric encephalopathy
  • Plasma membrane
  • Protein–protein interactions
Citation (ISO format)
SOLIS, Gonzalo et al. Pediatric encephalopathy: cinical, biochemical and cellular insights into the role of Gln52 of GNAO1 and GNAI1 for the dominant disease. In: Cells, 2021, vol. 10, n° 10, p. 2749. doi: 10.3390/cells10102749
Main files (1)
Article (Published version)
ISSN of the journal2073-4409

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