Mechanisms of Brain Dysmorphology in MN1 C-Terminal Truncation Syndrome, a Novel Intellectual Developmental Disability Disorder

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Project Summary – Research Project The mechanisms underlying Intellectual and Developmental Disabilities (IDDs) remain largely unknown. A substantial number of individuals with IDDs have developmental brain malformations which are associated with considerable morbidity and mortality. This proposal focuses on a newly identified IDD condition (MCTT syndrome), characterized by IDD, epilepsy, characteristic craniofacial differences, and two important brain malformations: polymicrogyria (PMG) and rhombencephalosynapsis (RES). PMG is a common feature in many IDDs and is strongly associated with developmental disability and epilepsy. Although PMG is known to be due to aberrant neuronal migration, the causes and molecular mechanisms remain incompletely understood, and few good animal models exist. RES is a unique cerebellar malformation characterized by fusion of the cerebellar hemispheres with partial or complete absence of a recognizable cerebellar vermis; almost nothing is known about the causes and mechanisms underlying RES, and no animal models exist. This project represents a synergistic collaboration between human and mouse model-focused investigators with support from three IDDRC Cores (Genetics, Brain Imaging, and Animal Behavior). At the completion of this project, we will understand the effects of C-terminal truncating MN1 variants on gene regulation and brain development. Our specific aims are: 1. To dissect the role of MN1 in transcriptional regulation using stem cell derived models; 2. To dissect the developmental mechanisms underlying MN1- related PMG and RES in mice.