Wednesday, April 19, 2006

Neuregulin: Monster gene of madness

Neuregulin is a massive and complex gene that produces six proteins in the brain. Protein four is found to be over-expressed in some schizophrenic patients, possibly due to a point mutation in a regulatory gene.
Schizophrenia as Misstep by Giant Gene - New York Times

... Neuregulin is one of about 10 genes so far linked to schizophrenia ... It is one of the largest genes in the human genome, sprawling over some 1,125,000 units of DNA, and it generates at least six types of protein ...

... the variant stretch of DNA ... linked to schizophrenia does not lie in the neuregulin gene itself but just upstream of it, meaning that it presumably affects not the actual proteins produced by the gene but the way the gene is controlled.

... the first component of the transcript that makes the Type 4 proteins lies at the very beginning of the neuregulin gene and closest to the upstream genetic segment that is statistically linked to schizophrenia.

The researchers found that people who inherited two versions of the variant segment, one from each parent, were producing 50 percent more of neuregulin's Type 4 protein than those who inherited one or no copies.

... The role of neuregulin's Type 4 proteins is unknown, but they may be involved in making neurons migrate, a property of great importance when the brain is being constructed.

Dr. Law said that the variant segment linked to schizophrenia had a single DNA unit change at the center of one of the binding sites recognized by the transcription factors that control the gene. Loss of the binding site presumably upsets the regulation of the gene, causing too much of the Type 4 protein to be generated, she said.

Having slightly more than usual of a single protein may seem a very subtle derangement for so devastating a disease, but subtlety is to be expected, Dr. Weinberger said. "We know that all mental illnesses are about very subtle aspects of the wiring biases. They are about how you process complicated environmental stimuli, not about how you walk down the street.

It's extremely difficult to make a functioning brain. Autism, schizophrenia, mental retardation, all are felt to be related to possibly minor defects in brain development. Given how hard it is to make the brain work "out of the box", I'd bet there are a vast array of corrective processes that take place until the brain matures -- at age 25 or so in men, earlier in women. Some of the disorders we see may represent partial failures, and partial successes, of repair processes. (ie. sacrificing the mirror neuron network to support the primary neuron network ...)

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