Opitz G/BBB Syndrome (OS) is a genetic disorder characterized by midline developmental defects. Male patients with the X-linked form of OS, caused by loss-of-function mutations in the MID1 gene, show high variability of the clinical signs. MID1 encodes an ubiquitin ligase that controls Phosphatase 2A but its role in the pathogenesis of the disease is still unclear. Here I report a mouse line carrying a non-functional ortholog of the human MID1 gene, Mid1. Mid1 null mice show the brain anatomical defect observed in patients, i.e. hypoplasia of the anterior portion of the medial cerebellum, the vermis. We found that the presence of this defect correlates with motor coordination, procedural and non-associative learning impairments. The defect is limited to the most anterior lobes of the vermis, the region of the developing cerebellum adjacent to the dorsal midbrain. Analyses at mid-gestation reveal that lack of Mid1 causes the shortening of the posterior dorsal midbrain; the rostralization of the midbrain/cerebellum boundary; and the down-regulation of a key player in the development of this region, Fgf17. Thus, lack of Mid1 causes a mis-specification of the midbrain/cerebellar boundary that results in an abnormal development of the most anterior cerebellar lobes. This animal model provides a tool for further in vivo studies of the physiological and pathological role of the Mid1 gene and a system to investigate the development and function of anterior cerebellar domains
