FMRP is a multifunctional protein essential for normal brain development and neuronal plasticity. Mutations, predominantly noncoding CGG-repeat expansions, within FMR1 (the gene that encodes FMRP) give rise to fragile X syndrome (FXS), the leading heritable form of intellectual disability and the most common single-gene cause of autism spectrum disorder (ASD).

Among its diverse functions, FMRP binds to and modulates multiple ion channels, including big-conductance voltage-activated potassium (BK) channels. Visual spatial deficits, coupled with electroretinogram (ERG) abnormalities, are observed in Fmr1 knockout mice¹. ERG deficits, specifically reduced b-waves to single flash and reduced amplitude to flicker trains of flashes, are also observed in males with FXS and people with premutations in FMR1². ERG abnormalities have also been observed in people with mutations in BK channels³, which is normally regulated by FMRP. This non-invasive measure may thus serve as a biomarker of altered central nervous system (CNS) function³.

The central hypothesis of the current project is that ERG abnormalities observed in FXS and people with premutations will be correlated with deficits in FMRP. FMRP levels in peripheral blood samples will be quantified using a newly developed application of time-resolved fluorescence resonance energy transfer (TR-FRET)⁴. This methodology has been previously used to define the relationship between FMRP levels and intelligence quotient (IQ). Further, ERG abnormalities are likely to be correlated with measures of IQ and sensory processing abnormalities and perhaps other behavioral differences, which will be assessed in the current study across the spectrum of fragile X mutations.

Thus, the proposed research will focus on linking a measure of CNS function (ERG activity) to molecular (FMRP levels) and neurobehavioral alterations in people with fragile X mutations. The findings are expected to lead to the identification of a biomarker that may be valuable as an outcome measure for assessing future treatments for FXS, premutation disorders and potentially other subtypes of ASD.

1. Rossignol R. et al. PLoS One 9, e105996 (2014) PubMed
2. Perche O. et al. J. Neurodev. Disord. 13, 45 (2021) PubMed
3. Perche O. et al. J. Med. Case Reports 16, 180 (2022) PubMed
4. Kim K. et al. PLoS One 14, e0226811 (2019) PubMed