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Autism, intellectual disability linked to levels of fragile X protein

People with particularly low levels of FMRP, the protein lacking in those with fragile X syndrome, are more likely to also have autism and severe intellectual disability, according to a new stud. The lower the level of FMRP, the more severe a person’s traits.

The findings could help researchers identify who would benefit most from certain treatments, says co-investigator Dejan Budimirovic, assistant professor of psychiatry and behavioral sciences at Johns Hopkins University in Baltimore, Maryland. They could also be used to design better outcome measures for pharmaceutical trials for the condition.

“This really helped us to work on closing a gap in the field” between a person’s traits and those traits’ molecular origins, Budimirovic says. “You really need to pair that with the clinical outcomes that can be translated to the bedside — that the clinicians and patients and families can see, ‘What does it mean to me?’”

Fragile X syndrome occurs when a section of the FMR1 gene, which codes for FMRP, contains more DNA ‘letter’ repeats than usual. The repeats silence the gene by driving DNA methylation: Molecules called methyl groups attach to a region of the gene where it can be switched on, blocking production of FMRP, a protein necessary for communication among neurons. Most people with the syndrome have intellectual disability (ID), and many also have autism.

The extent to which the methyl groups attach to the gene can vary among people with fragile X and from cell to cell, leading to different levels of FMRP in people with the same underlying genetics. The new work confirms the relationship between the number of repeats and an individual’s traits with greater precision than before: More repeats lead to more methylation, causing lower protein levels and more severe traits.

The findings confirm the chain of events that connect expanded repeats to the severity of traits seen in fragile X, and future treatments could potentially intervene anywhere along the chain, says David Amor, professor of clinical genetics at the Murdoch Children’s Research Institute in Victoria, Australia, who was not involved in the work. Amor worked on a separate October study that found that boys with fragile X with higher levels of methylation have lower cognitive abilities and more severe autism traits.

The new work also demonstrates the complexity of fragile X syndrome, Amor says: “Each affected individual probably has a unique molecular variant of the condition.”

Read the article in its entirety (written by Laura Dattaro) at Spectrum News.

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