Scores from the mother and the patient himself showed a high degree of agreement. with hypogammaglobulinemia and autism spectrum disorder shows a B cell developmental arrest and autistic-like behavior caused by abnormal development of the cerebellum and loss of ventral midbrain GABAergic neurons. Abstract The genetic causes of primary antibody deficiencies and autism spectrum disorder (ASD) AGN 192836 are largely unknown. Here, we report a patient with hypogammaglobulinemia and ASD who carries biallelic mutations in the transcription factor PAX5. A patient-specific mutant mouse revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia. 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 Rabbit Polyclonal to MRPL14 midbrain hubs, controlling motor function and reward processing, respectively. Heterozygous 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 AGN 192836 immunological and neurodevelopmental syndrome. Graphical Abstract Open in a separate window Introduction Autism spectrum disorder (ASD) refers to a heterogeneous continuum of neurodevelopmental abnormalities characterized by social, cognitive, and behavioral features, which include impaired communication skills, abnormal social interactions, and repetitive and stereotyped actions (Quesnel-Vallieres et al., 2019; Vorstman et al., 2017; Wang et al., 2014). The etiology of ASD has a strong genetic component, as 5% of ASD individuals carry de novo or inherited mutations in known ASD-causing loci, and single nucleotide or copy number variants in candidate ASD risk genes have been found in 25% of all ASD cases (Quesnel-Vallieres et al., 2019; Vorstman et al., 2017). Based on phenotypic heterogeneity and genetic complexity, ASD AGN 192836 is considered to be primarily a multifactorial disorder. has been identified as a candidate ASD risk gene by the discovery of heterozygous mutations in individuals with ASD (Gofin et al., 2022; Iossifov et al., 2012; ORoak et al., 2014; Stessman et al., 2017). Here, we demonstrate that mutations can cause a monogenic form of ASD. During embryogenesis, the transcription factor Pax5 is expressed, together with the related Pax2 protein, in the isthmic organizer at the midbrainChindbrain boundary (Urbnek et al., 1994) that controls the patterning and neuronal specification of the posterior midbrain and anterior hindbrain, from which the cerebellum develops (Zervas et al., 2005). mutant mice exhibit abnormal morphogenesis of the posterior midbrain and anterior cerebellum (Urbnek et al., 1994), while both the midbrain and cerebellum fail to develop in double-mutant embryos due to lack of the isthmic organizer (Schwarz et al., 1997). Within the hematopoietic system, Pax5 is exclusively expressed in the B lymphoid lineage (Fuxa and Busslinger, 2007), where it functions as an essential regulator of B cell commitment (Nutt et al., 1999), development (Horcher et al., 2001), and immunity (Caldern et al., 2021). At the molecular level, Pax5 performs a dual role in B lymphopoiesis by acting as a transcriptional repressor to suppress B lineageCinappropriate genes (Delogu et al., 2006; Revilla-i-Domingo et al., 2012) and as an activator to induce gene expression required for B cell development and function (Revilla-i-Domingo et al., 2012; Schebesta et al., 2007). In mature B cells, Pax5 additionally promotes phosphoinositide 3-kinase (PI3K) signaling by down-regulating expression of the phosphatase and tensin homolog (PTEN) protein, a negative regulator of this pathway (Caldern et al., 2021). Another important function of Pax5 is to suppress B cell tumorigenesis in mice (Cobaleda et al.,.
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