The genetic causes of primary antibody deficiencies and autism spectrum disorder (ASD) are largely unknown. Here, we report a patient with hypogammaglobulinemia and ASD who carries biallelic mutations in the transcription factor PAX5. A patient-specific Pax5 mutant mouse revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia. Pax5 mutant mice displayed behavioral deficits in all ASD domains. The patient and the mouse model showed aberrant cerebellar foliation and severely impaired sensorimotor learning. PAX5 deficiency also caused profound hypoplasia of the substantia nigra and ventral tegmental area due to loss of GABAergic neurons, thus affecting two midbrain hubs, controlling motor function and reward processing, respectively. Heterozygous Pax5 mutant mice exhibited similar anatomic and behavioral abnormalities. Lineage tracing identified Pax5 as a crucial regulator of cerebellar morphogenesis and midbrain GABAergic neurogenesis. These findings reveal new roles of Pax5 in brain development and unravel the underlying mechanism of a novel immunological and neurodevelopmental syndrome.

The authors regret that in the original version of Fig. 10 C, the Gad1&2, mCherry, and Pax5 smRNA-FISH data of the SN neuron had been accidentally copied from the bottom left row into the bottom right row. The corrected Fig. 10 C is shown here. The contours of the VTA neuron in the bottom right row remain unchanged, and the corrections do not alter the conclusions at the end of the Results section: "smRNA FISH analysis revealed concomitant expression of mCherry and Gad1, Gad2 mRNA in the VTA and SN in cells with and without active Pax5 expression (Fig. 10 C), demonstrating that GABAergic neurons in these regions without active Pax5 expression also originate from Pax5-expressing progenitor cells." The errors appear in print and in PDFs downloaded before December 1, 2022.