CNTNAP2 Variant Linked To Language Impairment

Today’s issue of Nature has a brief essay on the role of language in cultural evolution. The authors touch up on a lot basics, such as anatomical localization of brain activity related to language and tool making, FOXP2, and how language has helped humans pass on cultural information more effectively than any other form of communication. Overall, it is a well written review that I want to pass on.

Related, Erin from the Spitton, shared news of the identification of a new language related SNP on the gene CNTNAP2. The paper which reports this is titled, “A Functional Genetic Link between Distinct Developmental Language Disorders,” and was published in the New England Journal of Medicine. I believe it is open access, I got to the full text with no problem. The authors hypothesized that neural pathways downstream of FOXP2 can also affect language impairment.

To identify possible downstream candidates that might be involved in typical SLI, the authors transfected a human brain cancer cell line (SH-SY5Y) to continually express FOXP2. FOXP2 is a transcription factor, meaning it is a controller of the expression of other genes. If it is mutated, it can’t regulate its targets properly and leads to different, sometimes mutant, phenotype. The used a type of test called the chromatin immunoprecipitation (ChIP) assay which identifies how and often where proteins, like the FOXP2 transcription factor, bind to specific regions of the genome. This is done by using specific antibodies that recognize a specific protein or a specific modification of a protein, in this situation anti-FOXP2 antibodies.

The ChIP assay showed that the FOXP2 transcription factor binds to a particular, novel region of interest, the first intron of gene CNTNAP2. When transcribed and translated, CNTNAP2 normally encodes for the protein CASPR2 — a protein that is localized and understood to function in the nodes of Ranvier on myelinated neurons. Of further interest, CNTNAP2 is expressed in the human cerebral cortex, specifically the orbital gyrus and superior frontal anlage, spanning the inferior and middle frontal gyri — all regions know to related to language cognition.

To make sure that FOXP2 was for sure targeting this region, and wasn’t mislead due to any conformational changes that came from the antibody it was complexed with, the authors did some PCR and sequencing and saw that this region of interest, intron 1, does have matching known consensus, binding sequence for FOXP2. They did some other tests that shows that this sequence is highly specific to FOXP2… all of which suggests that this site on CNTNAP2 is definitively a binding site for FOXP2 (CAAATT).

The authors next varied the amount of FOXP2 expression and tried to see if it affects the ultimate expression of CNTNAP2. They were able to show there is a correlation — CNTNAP2 transcript levels were lowest where there are higher levels of FOXP2, suggesting that FOXP2 down regulates CNTNAP2. We haven’t know about FOXP2-CNTNAP2 interactions before, because FOXP2-bound fragment of CNTNAP2 is outside of the classically defined regulatory regions that promoter based microarrays identify… So identifying this pathway is very commendable.

With this downstream candidate gene isolated the authors moved to see how polymorphisms in CNTNAP2 manifest language phenotypes. Their population sample was made up from children from 184 different families where at least one child had a specific language impairment (SLI). The children had wildtype FOXP2, but children who carried the guanine nucleotide at rs17236239 SNP on CNTNAP2 had worse scores on a test that measures their ability to reproduce nonsense words like “brufid” and “contramponist.”

Now don’t get me wrong, this SNP, rs17236239, ain’t on intron 1 — where FOXP2 binds. FOXP2 was used as bait to fish out what gene bites to it. When CNTNAP2 was figured out to be a new novel target of FOXP2, the authors tried to see if CNTNAP2 variations also affect language. And they do. What’s also of interest is that other SNPs in the same regaion that rs17236239 is found also have CNTNAP2 as been linked to delayed speech in children with autism.

I’m really impressed with this paper. It’s a gem. Well written and straight forward. I don’t regularly read papers of such caliber, to be honest… So I really appreciate when I do. The new language related gene is also very important as we begin to piece together the complex network of genes and proteins, anatomy and behaviors that have allowed us to have language and use it.

    Eörs Szathmáry, Szabolcs Számadó (2008). Being Human: Language: a social history of words Nature, 456 (7218), 40-41 DOI: 10.1038/456040a
    S. C. Vernes, D. F. Newbury, B. S. Abrahams, L. Winchester, J. Nicod, M. Groszer, M. Alarcon, P. L. Oliver, K. E. Davies, D. H. Geschwind, A. P. Monaco, S. E. Fisher (2008). A Functional Genetic Link between Distinct Developmental Language Disorders New England Journal of Medicine DOI: 10.1056/NEJMoa0802828

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