Modelling a pathological GSX2 variant that selectively alters DNA binding reveals hypomorphic mouse basal ganglia and hindbrain defects.

Abstract

Gsx2 is a homeodomain transcription factor critical for development of the ventral telencephalon and hindbrain of the mouse. Loss of Gsx2 function results in severe basal ganglia dysgenesis as well as defects in the nucleus tractus solitarius (nTS) of the hindbrain together with respiratory failure at birth. De Mori et al. (2019) reported two patients with severe dystonia and basal ganglia dysgenesis that encode distinct recessive GSX2 variants, including a missense mutation within the homeodomain (GSX2Q251R). Hence, we modelled the homologous Gsx2 mutation (i.e. Gsx2Q252R) in mouse and our biochemical analysis revealed this variant selectively altered DNA binding. Moreover, mice carrying the Gsx2Q252R allele exhibited basal ganglia dysgenesis, albeit to a lesser extent than Gsx2 null mice. A notable difference between Gsx2Q252R and Gsx2 null mice was that Gsx2Q252R mice survive, and hindbrain analysis revealed relative sparing of the glutamatergic nTS neurons and catecholaminergic A1/C1, A2/C2 groups. Thus, the Gsx2Q252R variant is a hypomorph that compromises a subset of Gsx2-dependent neuronal subtypes and highlights a critical role for distinct thresholds of catecholaminergic and/or glutamatergic nTS neurons for viability.