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Untranslated Region Variant in FMR1 Eliminates Neuronal Activity

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Untranslated Region Variant in FMR1 Eliminates Neuronal Activity A3′ untranslated region variant in FMR1 eliminates PNAS PLUS neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR Joshua A. Suhla, Ravi S. Muddashettyb, Bart R. Andersona,b, Marius F. Ifrimb, Jeannie Visootsaka, Gary J. Bassellb, and Stephen T. Warrena,c,d,1 aDepartment of Human Genetics, Emory University, Atlanta, GA 30322; bDepartment of Cell Biology, Emory University, Atlanta, GA 30322; cDepartment of Biochemistry, Emory University, Atlanta, GA 30322; and dDepartment of Pediatrics, Emory University, Atlanta, GA 30322 Contributed by Stephen T. Warren, October 14, 2015 (sent for review September 29, 2015; reviewed by Claudia Bagni and Kimberly M. Huber) Fragile X syndrome is a common cause of intellectual disability and and is thought to be a principal cause of the cognitive disabilities in autism spectrum disorder. The gene underlying the disorder, fragile FXS patients (12, 18, 19). Whereas the effects of lacking FMRP X mental retardation 1 (FMR1), is silenced in most cases by a CGG- entirely have been extensively investigated, few studies have focused repeat expansion mutation in the 5′ untranslated region (UTR). Re- on the consequences of still-present but dysregulated translation cently, we identified a variant located in the 3′UTR of FMR1 enriched of FMRP. among developmentally delayed males with normal repeat lengths. Despite significant analysis of the FMR1 gene, only a small A patient-derived cell line revealed reduced levels of endogenous number of conventional genetic mutations, such as point muta- fragile X mental retardation protein (FMRP), and a reporter contain- tions and insertions/deletions, have been reported to be associ- ing a patient 3′UTR caused a decrease in expression. A control re- ated with FXS or developmental delay (20–27). To identify porter expressed in cultured mouse cortical neurons showed an causes of developmental delay attributable to FMR1 variants expected increase following synaptic stimulation that was absent other than the repeat expansion, our group sequenced the FMR1 when expressing the patient reporter, suggesting an impaired re- gene in 963 developmentally delayed males, each of whom tested sponse to neuronal activity. Mobility-shift assays using a control negative for the CGG expansion mutation, and discovered a number NEUROSCIENCE – RNA detected an RNA protein interaction that is lost with the pa- of previously unreported variants (28). However, the molecular tient RNA, and HuR was subsequently identified as an associated consequences, if any, of most of these variants remain unknown. protein. Cross-linking immunoprecipitation experiments identified In this study, we describe the functional impact of a variant the locus as an in vivo target of HuR, supporting our in vitro find- in the 3′UTR of FMR1 (c.*746T>C) using genetic, biochemi- ings. These data suggest that the disrupted interaction of HuR im- cal, and cell biological approaches. The variant is associated pairs activity-dependent translation of FMRP, which may hinder with reduced basal FMRP levels and impairs the normal re- synaptic plasticity in a clinically significant fashion. sponse to activity-dependent synaptic translation in cultured fragile X syndrome | FMR1 | FMRP | HuR | autism primary neurons. Our data suggest that the RNA-binding protein HuR binds the locus normally but that this association is lost when the variant is present, leading to destabilized and ragile X syndrome (FXS) is one of the most common forms of rapidly degraded FMR1 transcript. These findings indicate that inherited intellectual disability, and represents a well-known F the c.*746C variant allele, detected at a frequency of 1 in 160 genetic cause of autism spectrum disorder. FXS is a monogenic disorder characterized by the loss or dysfunction of the fragile X mental retardation protein (FMRP), the product of the fragile X Significance mental retardation 1 (FMR1) gene (1). In a vast majority of FXS patients, FMRP expression is absent due to the expansion of an The fragile X mental retardation protein (FMRP) is most highly unstable CGG repeat in the promoter region of the FMR1 gene. expressed in neurons, and is critical for proper synaptic function- This repeat tract is polymorphic in the population, where 5–45 ing. Fragile X syndrome, a common cause of intellectual disability, CGG repeats are typical. FXS patients have in excess of 200 is the result of absent or dysfunctional FMRP, highlighting its repeats, referred to as the full mutation (2), usually inherited via importance to the processes underlying learning and memory. A an unstable maternal premutation allele (55–200 repeats). At the rapid upregulation of FMRP synthesis at the synapse in response full mutation length threshold of ∼200 repeats, an epigenetic to specific neuronal signals is a key step in maintaining a dynamic event manifests that results in hypermethylation of the FMR1 synapse, although the mechanisms governing this up-regulation promoter region and subsequent silencing of the transcript and are not well-understood. We show that a variant in the 3′UTR protein expression (3–5). of fragile X mental retardation 1 (FMR1) causes the loss of this Studies of FMRP function suggest that it is a selective RNA- characteristic increase in synaptic FMRP synthesis, which may binding protein (RBP) that primarily acts as a negative regulator of lead to developmental delay in patients. These data identify translation (6, 7), and is estimated to associate with about 4–5% of several mechanisms and molecules modulating activity-de- mRNA messages expressed in the brain, including its own transcript pendent translation of FMRP. (8–10). FMRP is also a key regulator of translation downstream of glutamate receptor-mediated signaling in neurons, where it is rap- Author contributions: J.A.S., B.R.A., M.F.I., G.J.B., and S.T.W. designed research; J.A.S., R.S.M., B.R.A., and M.F.I. performed research; R.S.M. and J.V. contributed new reagents/analytic idly inactivated by dephosphorylation upon receptor activation, tools; J.V. provided clinical support; J.A.S., B.R.A., G.J.B., and S.T.W. analyzed data; and thereby allowing protein synthesis of its targets to occur in response J.A.S., G.J.B., and S.T.W. wrote the paper. to the stimulus (11–14). The absence of FMRP uncouples gluta- Reviewers: C.B., Catholic University of Leuven Medical School; and K.M.H., University of mate receptor stimulation from the protein synthesis typically re- Texas Southwestern Medical Center. quired for proper signal transduction at the synapse (15). These The authors declare no conflict of interest. molecular defects are associated with impaired synaptic plasticity, 1To whom correspondence should be addressed. Email: [email protected]. widely believed to underlie the processes of learning and memory, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. which requires tightly controlled synaptic protein synthesis (16, 17) 1073/pnas.1514260112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1514260112 PNAS Early Edition | 1of9 Downloaded by guest on September 29, 2021 developmentally delayed male patients tested (28), may repre- conserved evolutionarily, as indicated by PhyloP (31) (2.76), GERP sent an unrecognized genetic basis of developmental delay via (32) (5.52), and PhastCons (33) (1.00) scores. Last, the locus is FMR1 dysregulation. thymine- and uridine-rich at the RNA level, which we hypothe- sized could serve as a site of interaction for a class of U-rich RBPs Results (Fig. S1). Based on these data, we explored whether the variant Clinical Assessment of a Patient with the c.*746T>C Variant. One of had any effect on FMRP expression in the patient. A lympho- the patients identified by Collins et al. (28) as harboring the blastoid cell line was established from the patient’sbloodand c.*746T>C variant was clinically evaluated by the Emory University Western blot analysis revealed a modest, but significant, reduction Medical Genetics Clinic. The patient (pictured in Fig. 1A) was of the patient’s endogenous FMRP level compared with two ∼10.5 y old at evaluation and was born full-term at 10 lb, 1 oz healthy lymphoblastoid control lines (Fig. 1B). To corroborate without complication. He was reported to have sat independently these results, luciferase reporter vectors were constructed to in- at 17 mo [typically achieved by 9 mo of age (29)] and first walked clude the full-length FMR1 3′UTR of the patient or a healthy at 24 mo [typically achieved by 18 mo of age (29)]. At examination, control downstream of the firefly luciferase gene. We observed a he was nonverbal and exhibited stereotypic behavior consisting of significant decrease in normalized luciferase signal with the patient rocking, spinning, rubbing his fingers, and repetitively touching his reporter compared with the control in two different cell lines (P = shirt collar. The patient had previously been diagnosed with au- 0.007 in HEK293FT; P = 0.004 in Neuro2a; Fig. 1C). Additionally, tism spectrum disorder and attention deficit hyperactivity disorder the 3′UTR from the patient’s affected half-sibling brother, who (ADHD), and he attends special education classes. Cognitive abil- harbored the c.*746C allele as well, showed a similar reduction in ities were assessed using the Stanford–Binet Intelligence Scales luciferase activity compared with the control (P < 0.001; Fig. 1D). (5th Ed) (30), revealing moderate intellectual disability (IQ score Steady-state levels of luciferase transcript were equivalent between 47). In terms of his growth parameters, the patient is within the 50– the patient and control vectors (Fig. S2), suggesting a posttran- 75th percentiles for weight (88 lb), height (60 in), and head cir- scriptional mechanism underlying the reduction in patient reporter cumference (55 cm). A physical examination was performed activity. However, other mechanisms, such as mRNA instability, where bilateral flat feet with inversion were noted but no other may be responsible for the observed decrease in luciferase ac- significant findings.
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