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Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Research group De Zeeuw
Publication year 2022
Published in Journal of Experimental Medicine
Authors Fabian M P Kaiser, Sarah Gruenbacher, Maria Roa Oyaga, Enzo Nio, Markus Jaritz, Qiong Sun, W. Van der Zwaag, Emanuel Kreidl, Lydia M Zopf, Virgil A S H Dalm, Johan J Pel, Carolin Gaiser, Rick van der Vliet, Lucas Wahl, André Rietman, Louisa Hill, Ines Leca, Gertjan Driessen, Charlie Laffeber, Alice Brooks, Peter D Katsikis, Joyce H G Lebbink, Kikuë Tachibana, Mirjam van der Burg, C.I. De Zeeuw, Aleksandra Badura, Meinrad Busslinger

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.

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