The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects.

The missense mutation Y65C in polyglutamine-binding protein 1 (PQBP1) is associated with Renpenning syndrome, characterized by X-linked intellectual disability and microcephaly. However, the pathogenic mechanism underlying the microcephaly induced by the Y65C mutation remains unclear. In this study, we generated Pqbp1Y65C/Y knock-in male mice and discovered that the Y65C mutation impairs the proliferation of apical progenitors and their subsequent transition to basal progenitors, resulting in microcephaly and cognitive deficits like those observed in Renpenning syndrome patients. This Y65C substitution induces PQBP1 misfolding, which reduces PQBP1 protein levels and consequently impedes apical progenitor proliferation. Unexpectedly, the Y65C mutation also induces a gain-of-function that interferes with the transition from apical to basal progenitors by enhancing interactions with the core components of the mRNA 3' end processing machinery, thereby preserving proliferative alternative polyadenylation (APA) profiles. Our study demonstrates that a combination of loss-of-function and gain-of-function contributes to the microcephaly caused by the Y65C mutation.