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 for proper forebrain, testisandpancreasdevelopment.Polyalanineexpansionsaccountfor over half of all mutations inARXand clinically give rise to a spectrumof IDand seizures. To understand how the polyalanine expansions cause the clinical phenotype,we studiedmousemodelsof the twomost frequent polyalanine expansion mutations (Arx^(GCG)7 and Arx^432-455dup24). Neithermodelshowedevidenceof protein aggregates;however, a marked reduction of Arx protein abundance within the developing forebrainwas striking. Examining the expression ofknownArxtargetgenes,wefoundamore prominent loss ofLmo1repression in Arx^(GCG7)/Ycomparedwith Arx^{432-455dup24/Y} mice at 12.5 and 14.5 dpc, stages of peak neural proliferation and neurogenesis, respectively. Onceneurogenesis concludes both mutantmousemodelsshowedsimilar 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^(GCG)7 and Arx^432-455dup24 mouse models. It is yet to be determined what effect these mutations have on ARX protein in affected males in the human setting.