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Size matters: Variants in the MECP2 gene are associated with a smaller cortical surface area, even in healthy men.
Small, common variations in MeCP2 — a gene that’s severely mutated in individuals with Rett syndrome — can subtly affect brain structure even in normal individuals, according to a study published in August in the Proceedings of the National Academy of Sciences1.
Researchers found that a set of 11 single- nucleotide changes in and around MeCP2, which are inherited as a group, correlate with a smaller cortical surface area in men from Norwegian and North American groups. Unlike previously characterized mutations in the gene, these variants are found throughout the population and are not tied to obvious behavioral or cognitive symptoms.
“To see that there are apparently [MeCP2] subtypes that influence cortical area is very interesting,” says Columbia University neuroscientist David Sulzer, who was not involved in the study. “Problems with the cortex may often be causes of autism.”
MeCP2 is known to be important for brain development. Severe, rare MeCP2 mutations, including deletions, lead to Rett syndrome, an autism-like condition that predominantly affects girls and is characterized by repetitive behavior and language delay.
Past studies have also detected pronounced brain size changes in mice2 and humans3 with MeCP2 mutations.
But this is the first time anyone has shown that single-nucleotide changes in the MeCP2 region, found across the general population, can alter brain size. Lead investigator Nicholas Schork, director of research at Scripps Genomic Medicine in La Jolla, California, and his colleagues are searching for additional MeCP2 mutations in autism.
There is a history of brain size changes in autism, says Anthony Wynshaw-Boris, a neurogenetics researcher at the University of California, San Francisco, who was not involved in the study. “Clearly, any genes that are related to brain size may have relevance,” he says.
Found on the X chromosome, the MeCP2 gene codes for a regulatory protein called methyl CpG binding protein 2, thought to be a master regulator of thousands of other genes.
Schork and his colleagues assessed brain size and shape in a group of Norwegians — 187 with psychotic disorders and 102 healthy controls — and looked for single-nucleotide polymorphisms, or SNPs, in and around the MeCP2 gene.
They detected a correlation between a set of 11 SNPs and cortical surface area in both the psychotic disorder and control groups, but only in the men.
In particular, they found that a SNP called rs2239464 is more common in men with a smaller surface area across the cortex — a brain region involved in language, memory and other higher brain functions. Unlike previously detected mutations, the variants don’t truncate the MeCP2 protein.
Gender bias:
It’s not yet clear why brain size is only affected in men: The researchers say it could be the result of hormonal differences or gender-specific MeCP2 regulation, or perhaps because a copy of MeCP2 on the second X chromosome in women compensates for the protein’s function.
The researchers used refined imaging techniques to detect the small cortical surface area changes — between about two and six percent. They found the same correlation in a follow-up study of 468 North Americans with mild cognitive impairment or Alzheimer’s disease and 187 healthy controls, independent of age and disease status.
Even so, Schork says, links between the SNPs and cortical surface area cannot be carried over to other populations without additional studies, because individuals with different ancestry frequently show distinct genetic associations.
For instance, one of the SNPs in the study is found in a minority of individuals of European descent, but is more common in Han Chinese and Yoruban African populations.
More evidence is also necessary to show that the association is causative and not just correlative, notes Sulzer. “This suggests to me — but does not prove — that different genetic variations in MeCP2 might or might not change overall cortical area,” Sulzer says.
It’s tricky to interpret the new study because the SNPs don’t lead to detectable behavioral or phenotypic differences, adds Janine LaSalle, a professor of medical microbiology and immunology at the University of California, Davis.
It is also unclear why the effect is restricted to men, or how the SNPs might alter MeCP2’s function, she says.
Still, because MeCP2 is a master regulator of other genes, it’s feasible that even minor changes in the gene could have widespread effects. “If MeCP2 is even a little bit altered by polymorphisms, that could alter that whole chain of events,” LaSalle says.
Schork and his colleagues are trying to unravel the functional and phenotypic consequences of the common variants. They are also sequencing the MeCP2 region in roughly 50 children with autism and unaffected controls.
Common MeCP2 variants have not shown up in large genome-wide association studies of autism4, so it’s unlikely any of the common variants tested so far are strongly associated with the disorder, Schork says.
Still, he says, it’s possible that there are MeCP2 variants more benign than those detected in Rett syndrome, but more deleterious than those in this study, that contribute to autism.
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