Increasing our understanding of human cognition through the study of fragile X syndrome

Abstract

Fragile X Syndrome (FXS) is considered the most common form of inherited intellectual disability. It is caused by reductions in the expression level or function of a single protein, the Fragile X Mental Retardation Protein (FMRP), a translational regulator which binds to approximately 4% of brain messenger RNAs. Accumulating evidence suggests that FXS is a complex disorder of cognition, involving interactions between genetic and environmental influences, leading to difficulties in acquiring key life skills including motor skills, language, and proper social behaviors. Since many FXS patients also present with one or more features of autism spectrum disorders (ASDs), insights gained from studying the monogenic basis of FXS could pave the way to a greater understanding of underlying features of multigenic ASDs. Here we present an overview of the FXS and FMRP field with the goal of demonstrating how loss of a single protein involved in translational control affects multiple stages of brain development and leads to debilitating consequences on human cognition. We also focus on studies which have rescued or improved FXS symptoms in mice using genetic or therapeutic approaches to reduce protein expression. We end with a brief description of how deficits in translational control are implicated in FXS and certain cases of ASDs, with many recent studies demonstrating that ASDs are likely caused by increases or decreases in the levels of certain key synaptic proteins. The study of FXS and its underlying single genetic cause offers an invaluable opportunity to study how a single gene influences brain development and behavior. © 2013 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 74: 147–177, 2014

Identification of Wilms' Tumor 1-associating Protein Complex and Its Role in Alternative Splicing and the Cell Cycle

“…FMRP has been implicated in translational control, associating with actively translating polyribosomes in ribonucleoprotein particles (reviewed in Ref. 39). ERH is a highly conserved protein that has been implicated in nuclear gene expression (40,41) and cell growth (42)(43)(44).…”

FXR1P Limits Long-Term Memory, Long-Lasting Synaptic Potentiation, and De Novo GluA2 Translation

“…All three proteins associate with polyribosomes and messenger ribonucleoprotein particles (mRNPs), are found at spines, and are expressed in similar patterns in the brain, presenting the question of whether they perform redundant functions (Cook et al, 2014; Tamanini et al, 1997, 2000). However, until now, nothing was known about the mRNA targets of FXR1P or its role in the brain.…”

Deletion of <b><i>TOP3B</i></b> Is Associated with Cognitive Impairment and Facial Dysmorphism

“…They proposed that TOP3B actually participates in mRNA metabolism as well as DNA processing because TOP3B was found to be associated with the fragile X mental retardation protein (FMRP), an mRNA-binding protein that interacts with polyribosomes and regulates translation. The FMRP is encoded by the FMR1 gene, mutations in which cause fragile X syndrome (OMIM #300624), a genetic condition that involves developmental delays, learning disabilities, autism, attention deficit disorder, and characteristic physical features such as large ears, craniofacial features, macroorchidism, and hyperflexible fingers [Cook et al, 2014]. The detailed studies of Stoll et al [2013] found that TOP3B plays a role in the metabolism of FMRP-bound mRNAs.…”