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

Fabian M.P. Kaiser, Sarah Gruenbacher, Maria Roa Oyaga, Enzo Nio, Markus Jaritz, Qiong Sun, Wietske van der Zwaag, Emanuel Kreidl, Lydia M. Zopf, Virgil A.S.H. Dalm, Johan Pel, Carolin Gaiser, Rick van der Vliet, Lucas Wahl, André Rietman, Louisa Hill, Ines Leca, Gertjan Driessen, Charlie Laffeber, Alice BrooksPeter D. Katsikis, Joyce H.G. Lebbink, Kikuë Tachibana, Mirjam van der Burg, Chris I. De Zeeuw, Aleksandra Badura*, Meinrad Busslinger*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article numbere20220498
JournalJournal of Experimental Medicine
Issue number9
Publication statusPublished - 5 Sept 2022

Bibliographical note

Funding Information:
This research was supported by Boehringer Ingelheim (M. Busslinger), the Austrian Research Promotion Agency (Early Stage Grant “Molecular Control” FFG-878286, M. Busslinger), the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement 740349 [to M. Busslinger] as well as 737619 and 768914 [to C.I. De Zeeuw]), the Stichting Sophia Kinderziekenhuis Fonds (grant no. S15-07; M. van der Burg and G. Driessen), the Erasmus MC Department of Immunology (F.M.P. Kaiser and P.D. Katsi-kis), the Gravitation program from the Netherlands Organization for Scientific Research (NWO), part of the Oncode Institute, partly financed by the Dutch Cancer Society (J.H.G. Lebbink and C. Laffeber), NWO-ALW (grant 824.02.001; C.I. De Zeeuw), the Dutch Organization for Medical Sciences (ZonMw-91120067; C.I. De Zeeuw), Medical Neuro-Delta (MD 01092019-31082023; C.I. De Zeeuw), INTENSE LSH-NWO (TTW/00798883; C.I. De Zeeuw), NWO-VIDI (ZonMw-917.18.380,2018; A. Badura), and Erasmus MC grant (MRACE Pilot 2019; A. Badura).

Publisher Copyright:
© 2022 Kaiser et al.


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