New Blood Sample Methods Link IQ Scores, FMRP Protein Levels

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A team led by researchers at Fulcrum Therapeutics has developed new methods to measure the FMRP protein in blood cells.

Using these tests, the scientists showed that FMRP levels in blood cells were statistically associated with intelligence quotient (IQ) scores among people with fragile X syndrome.

The study, “FMRP Levels in Human Peripheral Blood Leukocytes Correlates with Intellectual Disability,” was published in Diagnostics.

Fragile X is caused by genetic mutations in the gene FMR1, which provides instructions for making a protein called FMRP that is important for maintaining the health of connections among nerve cells.

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Fragile X symptoms are mainly caused by too-little FMRP protein in nerve cells. As such, measuring FMRP levels in these cells may be useful for quantifying the disease’s severity, or assessing the response to treatments that target its underlying cause. However, taking a sample of brain or nerve tissue to study isn’t feasible, since it would be invasive and unsafe.

A potential alternative is to measure FMRP levels in other, more easily accessible tissues.

“Repeated, accurate measurements of FMRP from accessible tissue could prove valuable in proof-of-concept studies of novel therapies to reactivate FMRP expression. In addition, FMRP levels themselves may be considered for use as an outcome measure in clinical trials,” the researchers wrote.

When it comes to taking cell samples from the body, the tissue of choice is usually the blood — blood draws are routinely done with most hospital work, samples are fairly easy to store, the procedure is very safe, and the body is constantly making more blood cells to replace those that are sampled, unlike with brain tissue.

Prior research sought to measure FMRP levels in peripheral blood mononuclear cells (PBMCs), a group that includes white blood cells. However, standard protein-detecting methods like Western blot and ELISA have not been shown to be able to reliably measure levels of this protein in PBMCs, specifically.

To overcome this problem, the researchers developed two new methods: an electro-chemiluminescence immunoassay and a multiparameter flow cytometry assay. Both employ antibodies that can stick to the FMRP protein, which can then be detected via sophisticated machines.

“[T]his study is of importance because the methods developed are sensitive and accurate to quantify FMRP, do not require many cells, are rapid and cost-effective, and can be easily implemented in most laboratories,” the researchers wrote. “Of extreme relevance is that this method works in blood (PBMCs); sampling the blood is minimally invasive and avoids the complications of biopsies or of other collection approaches.”

The assays were used to assess FMRP levels in PBMCs from 27 people — 23 with fragile X and four without, all males.

Both methods could accurately quantify FMRP levels, results showed. Both tended to yield similar values, and the protein levels detected were correlated with the severity of FMR1 mutations, as expected. Protein levels also correlated with levels of FMR1 mRNA, a molecule produced when the FMR1 gene is “read” to make the FMRP protein.

FMRP levels were significantly correlated with participants’ IQ — those with a higher IQ tended to also have higher FMRP levels in their PBMCs.

“These accurate FMRP measurements will be helpful in assessing the degree of FMRP deficiency in individuals with [fragile X] using readily obtainable clinical samples, in different tissues and developmental stages,” the researchers concluded, adding that the measurements also “could be used in prospective clinical trials to assess the role of FMRP as a biomarker of treatment efficacy.”