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Fishing for Genetic Links in Autism: Page 2 of 4

Fishing for Genetic Links in Autism: Page 2 of 4

There are many mechanisms to help this complex decide which gene to turn on. RNA polymerase II enzyme can be shown which genes it needs to turn on and which are supposed to be left alone. There are escort-like proteins that physically bind to the RNA polymerase II and guide the complex to its proper genetic destination. Another mechanism involves proteins that bind to the gene to be transcribed rather than to the RNA polymerase II. These proteins then act like homing beacons, guiding a wandering RNA polymerase II to its proper nucleotide destination. There are also repressor proteins that work in a similar but opposite fashion. They render a gene that could be activated into a repressed, transcriptionally inert state.

Histone protein complexes. Histones are groups of proteins around which DNA wraps, like twine around a ball. There are many of these wound-up balls along a chromosome that function like physical barriers. If the DNA that harbors a class II gene is wrapped around the histone complex, RNA polymerase II can have a very difficult time binding to it, and the gene is rendered silent. If the histone complex is bulldozed out of the way, the class II gene becomes available for activation.

Chromatin is a com­bination of DNA and histones: this mass of molecules can form surprisingly complex, higher-ordered structures. The structures are so specific that antibodies capable of binding to them can be created. The structures can then be individually isolat­ed intact through a protocol called “chro­matin immunoprecipitation.”

Methyl groups and methylation reactions. Methylation reactions involve adding a methyl group (CH3) to certain nucleotides in the double helix. If the methylation occurs on or near a class II gene, it can be rendered inactive.

How does this work? The methyl groups studded along the length of a gene often attract repressor proteins that perform the actual silencing function. Such repressor proteins are attracted to a given segment of DNA via sequences on the DNA called “CpGs” (sometimes referred to as CpG islands), which are short regions of DNA enriched for cytosine and guanine nucleotides (the “p” refers to the phosphodiester bond between cytosine and guanine). CpG islands often cluster at the promoter sites within the class II gene.

CREB. The last piece of background information is the biology of the CREB protein (which stands for the tongue-twisting name “cyclic AMP response element binding”). The characterization of CREB function is one of the great research achievements in all of molecular neurobiology. The reason? CREB is involved in activating the genes that take part in learning, and it does so in virtually every animal ever tested (including humans). It specifically activates gene sequences involved in establishing memory formation by binding to their promoter regions and transcriptionally activating the gene. CREB is a classic activator. Understanding the genes to which CREB normally binds has resulted in the isolation of many sequences in­volved in human learning. Understanding CREB bi­ology remains a subject of intense interest and plays a powerful role in our story.

MeCP2 and Rett syndrome
With this admittedly lengthy background information, we can return to the biology of the MeCP2 protein and its role in autistic spectrum disorders.

The MeCP2 gene was first characterized by researchers who were interested in Rett syndrome. An X-linked dominant disease, Rett syn­- drome affects 1 in 10,000 persons and is found mainly in females. Symptoms usually present within the first 6 to 18 months of life and include motor and speech difficulties, sei­zures, increasing cognitive impairment, and growth retardation. About half of those affected eventually become non­ambulatory and many have chronic GI disorders.

Several types of mutations have been characterized, from deletions and insertions to subtle point mutations (changes in single base pairs). Most germane to our story, MeCP2 mutations were eventually associated with certain autism spectrum disorders. While this association hardly represents the overarching genetic explanation for even a single autistic category, the finding was important. The function of MeCP2 is well known, and has been established in animal models that carry MeCP2 mutations. Having such a well-characterized ally could be useful in the understanding of autism.

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