Mouse study offers clues to Rett syndrome mutation differences

Researchers identified a genetic signature that explains why some people who carry certain mutations in the MECP2 gene, called C-terminal deletions (CTDs), develop Rett syndrome, while others do not.

The discovery’s clinical significance was demonstrated when a severe Rett mouse model, treated with a gene-editing strategy to convert a disease-causing CTD to a benign version, developed normally with no Rett-like symptoms.

“These findings define a reliable prognostic distinction between benign and [Rett-causing] CTDs and establish a potential editing strategy for correcting disease-causing CTD mutations,” the researchers wrote.

The study, “Translational reading frame predicts the pathogenicity of C-terminal frameshift deletions in MeCP2,” was published in the journal eLife.

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Understanding mutations

In most cases, Rett syndrome is caused when mutations in the MECP2 gene disrupt the production of MeCP2, a protein that normally helps regulate the activity of other genes, particularly in nerve cells. This impairs nerve cell communication and alters brain development, leading to Rett symptoms.

About 10% of Rett-causing mutations are CTDs, a class of mutations that remove a stretch of DNA near the end of the MECP2 gene, resulting in a shortened MeCP2 protein. There are more than 50 different CTDs in a Rett mutation database, RettBASE, and they are generally associated with milder disease.

Previous work by researchers at the University of Edinburgh and their collaborators examined mouse models carrying the two most common CTDs. One mouse model (CTD1) produced low MeCP2 levels and developed severe Rett-like disease, while another (CTD2) made functional MeCP2 and remained healthy.

And in the gnomAD database of human genetic variants from the general population, several individuals who carry CTDs similar to those seen in Rett patients show no signs of disease.

To understand why some CTDs cause Rett while others don’t, the team further examined data from RettBASE (now incorporated into ClinVar), gnomAD, and ExAC.

They found that the difference lay in how deletions created distinct ends of the shortened protein. Rett-causing MeCP2 ended with the amino acid sequence Pro-Pro, while the benign version ended with Ser-Pro-Arg-Thr. Amino acids are the building blocks of proteins.

To test this, the researchers created a mouse model, called CTD3, that recapitulated the benign CTD version. Consistently, these mice appeared identical to their normal littermates and showed no Rett-like symptoms. By contrast, CTD1 mice with the Pro-Pro ending had markedly reduced MeCP2 protein and died earlier.

A case study illustrated the clinical significance of this distinction: It described a girl thought to carry a Rett-causing CTD. Instead, she actually harbored the benign CTD and remained healthy at 10 months. Her unaffected father, mother, and brother also carried the same CTD.

The researchers suggested that production of a MeCP2 ending in Pro-Pro may slow or stall, triggering the degradation of the protein and its messenger RNA, the intermediate molecule that carries the instructions from genes to make proteins. Consistent with this, the CTD1 mouse brain showed reduced levels of MeCP2 mRNA and protein.

The team then tested a gene-editing approach to correct disease-causing CTDs in mice. The gene correction created a slightly longer MeCP2 with the terminal amino acid sequence Gln-Gly-Ala-Ser, instead of Pro-Pro. These new mice were indistinguishable from normal littermates, developed no Rett-like symptoms, and survived to at least one year of age.

“The present study provides a simple genetic explanation for the initially puzzling observation that CTDs in the human MECP2 gene cause [Rett] in some individuals but appear to be benign in others,” the researchers wrote. “Our DNA base editing strategy offers promise for future development as a therapeutic for [Rett] caused by CTD mutations.”