A gain-of-function mutation in the gene causes neurodevelopmental deficits.

OBJECTIVE

To identify inherited or de novo mutations associated with a suite of neurodevelopmental abnormalities in a 10-year-old patient displaying ataxia, motor and speech delay, and intellectual disability.

METHODS

We performed whole-exome sequencing of the proband and her parents. A pathogenic gene variant was identified as damaging based on sequence conservation, gene function, and association with disorders having similar phenotypic profiles. Functional characterization of the mutated protein was performed in vitro using a heterologous expression system.

RESULTS

A single de novo point mutation in the gene was identified as causative for the neurologic symptoms of the proband. The mutation is predicted to change a codon for alanine to that of a threonine at position 657 (A657T) in the GluK2 kainate receptor (KAR) subunit, a member of the ionotropic glutamate receptor gene family. Whole-cell voltage-clamp recordings revealed that KARs incorporating the GluK2(A657T) subunits show profoundly altered channel gating and are constitutively active in nominally glutamate-free extracellular media.

CONCLUSIONS

In this study, we associate a de novo gain-of-function mutation in the gene with deficits in motor and higher order cognitive function. These results suggest that disruption of physiologic KAR function precludes appropriate development of the nervous system.