Intellectual disability (ID), previously called Mental Retardation, is an untreatable neurological disorder that affects a significant portion of the population. ID is a major burden to the family as associated health care costs are high and patients with ID are frequently reliant upon family members for their activities of daily living. Little is known about how ID develops and one way to study this complex neurological disorder is to study families with inherited forms of ID. Therefore, we study families with recessive ID to identify gene mutations that underlie this disorder. Using advanced sequencing technology;we have identified a novel gene mutation in a family with ID. This novel gene is expressed almost exclusively in the developing brain and encodes a known regulator of the cellular cytoskeleton. We hypothesize that mutations in this gene alter the cytoskeleton of developing neurons and this leads to defects in synapse formation, neuronal wiring and subsequent neuronal function. To test this hypothesis, we propose the following three aims: 1. Characterize the spatial and temporal expression patterns of the gene in developing mouse neurons. 2. Understand how mutations in the gene alter dendritic spine structure in knockout mice and in patient neurons generated from fibroblast-derived induced pluripotent stem cells (iPSCs). 3. Study how mutations in this gene alter neuronal signaling in knockout mice and neurons derived from patient fibroblasts. Understanding the cellular and molecular mechanism that underlie the genetic causes of ID will eventually lead to much needed, targeted treatments for this often devastating disorder.
Intellectual Disability is a poorly understood disorder with multiple underlying causes. Intellectual Disability affects a significant percentage of the population and at present, no treatments exist for this often devastating disorder. This works seeks to explore the function of a newly identified gene that is mutated in families with inherited Intellectual Disability. We will study how mutations in this gene give rise to abnormalities in brain development using cell biology, animal models and patient-derived stem cells.