Reduced polyalanine-expanded Arx mutant protein in developing mouse subpallium alters Lmo1 transcriptional regulation

Intellectual disability (ID) is a highly prevalent disorder that affects 1–3% of the population. The Aristalessrelated homeobox gene (ARX) is a frequently mutated X-linked ID gene and encodes a transcription factor indispensable forproper forebrain, testisandpancreasdevelopment.Polyalanineexpansionsaccount foroverhalfof all mutations in ARX and clinically give rise to a spectrum of ID and seizures. To understand how the polyalanine expansions cause the clinical phenotype,we studied mouse models of the twomost frequent polyalanine expansion mutations (Arx and Arx).Neithermodel showedevidenceof protein aggregates;however, a marked reduction of Arx protein abundance within the developing forebrain was striking. Examining the expressionofknownArx targetgenes,wefoundamoreprominent lossofLmo1 repression inArx compared with Arx mice at 12.5 and 14.5 dpc, stages of peak neural proliferation and neurogenesis, respectively. Once neurogenesis concludes both mutant mouse modelsshowed similar loss ofLmo1 repression. Wepropose that this temporal difference in the loss of Lmo1 repression may be one of the causes accounting for the phenotypic differences identified between the Arx and Arx mouse models. It is yet to be determined what effect these mutations have on ARX protein in affected males in the human setting.