The identification of a novel KCNJ2 gain-of-function mutation links altered neuronal excitability in autism with cardiac potassium channelopathies like short QT syndrome.
p.Phe58Ser may link autism excitability changes to short QT; leaves open clinical validation.
Inwardly rectifying potassium channels have been historically associated to several cardiovascular disorders. In particular, loss-of-function mutations in the Kir2.1 channel have been reported in cases affected by Andersen-Tawil syndrome while gain-of-function mutations in the same channel cause the short QT3 syndrome. Recently, a missense mutation in Kir2.1, as well as mutations in the Kir4.1, were reported to be involved in autism spectrum disorders suggesting a role of potassium channels in these diseases and introducing the idea of the existence of K+ channelautism spectrum disorders. Here, we report the identification in an Italian affected family of a novel missense mutation (p.Phe58Ser) in the KCNJ2 gene detected in heterozygosity in a proband affected by autism and borderline for short QT syndrome type 3. The mutation is located in the N-terminal region of the gene coding for the Kir2.1 channel and in particular in a very conserved domain. In vitro assays demonstrated that this mutation results in an increase of the channel conductance and in its open probability. This gain-of-function of the protein is consistent with the autistic phenotype, which is normally associated to an altered neuronal excitability.
No takes yet. Share an insight, caveat, or question.
Binda et al. (2018) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: