Autism spectrum disorder (ASD) remains a medical enigma due to the many clinical forms, the rise in prevalence worldwide and the vast genetic heterogeneity involved. The laboratory of Stephen Scherer recently uncovered preliminary findings that identify the PTCHD1-antisense (AS) long noncoding RNA (lncRNA) gene, present on the X chromosome, as a bona fide susceptibility locus for ASD. Males who carry chromosome microdeletions of PTCHD1-AS present with either ASD or a milder form of the disorder referred to as ‘broader autism phenotype,’ while female carriers are unaffected. In individuals in which the deletion extends beyond PTCHD1-AS into the next gene (PTCHD1, which is protein coding), typically present with both ASD and intellectual disability. The strong genetic association of PTCHD1-AS with ASD has prompted Scherer and his group to initiate pilot studies in model systems to understand the functional consequences of mutations within this gene.

Scherer’s laboratory has generated induced pluripotent stem cell (iPSC)-derived neurons from two males with ASD and PTCHD1-AS deletions (one of these individuals having only exon 3 within PTCHD1-AS missing) and isogenic lines with exon 3 of PTCHD1-AS deleted. These iPSC-derived neurons demonstrate reductions in excitatory synaptic transmission. Recently, Scherer’s group also generated two Ptchd1-as mouse knockout lines, in which exon 3 was targeted. Consistent with PTCHD1-AS deletions being found in higher-functioning ASD individuals, a preliminary examination of these knockout mice uncovered social deficits and a stereotypic behavior without any concomitant deficits in motor function, anxiety or exploratory action.

In collaboration with a newly assembled multidisciplinary research team at the Hospital for Sick Children, Scherer proposes to extend these findings in order to decipher how the dysregulation of PTCHD1-AS contributes to ASD. To do so, Scherer’s team will (1) characterize additional novel Ptchd1-as mouse models and (2) delineate the role of PTCHD1-AS/Ptchd1-as in synaptic function. The study of the PTCHD1-AS lncRNA will provide a new entry point to discern critical molecular and physiological events underlying ASD pathogenesis. Decoding the role of PTCHD1-AS in ASD should also yield novel insight into its synaptic regulatory mechanisms and targets for therapeutic modulation.