Mutation location is the key to prognosis

The three most important factors in real estate are location, location, location, and the same might be said for mutations in the gene MECP2, said researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children's Hospital in a report in the journal Cell.

"Where a mutation occurs can affect the severity of the symptoms of the disease," said Dr. Huda Zoghbi, professor of molecular and at BCM and director of the NRI. Zoghbi, corresponding author of the report, found the MECP2 gene in 1999 and confirmed that deficiency in the protein causes Rett syndrome, a post natal genetic disease that mainly affects girls.

In the study, she and her colleagues relied on data from rare with disruptions in MECP2 that showed that severity of symptoms could be influenced by the location of the . The few boys with this disorder fell into two broad categories: Those who suffered severe and death before age 4 and those who lived for decades with symptoms similar to that of Rett or and other disorders similar to those seen in autism.

Looking at the placement of the mutations in the boys, they hypothesized there was a distinct difference in symptoms seen in boys who had mutations at amino acid 270 in the protein and those who had mutations only slightly farther along, at amino acid 273. The protein is truncated or shorter in those with amino acid 270 mutations than those with the mutation at amino acid 273.

After Steven Baker, a graduate student in the Program in at BCM, generated and characterized mice that had mutations at the two sites of the protein, he found that mice who had mutations at amino acid 273 lived longer and developed symptoms later than those mice who had mutations at amino acid 270 or those who lacked the MeCP2 protein all together (knock-out mice).

One reason for the differences could be that the mutation at amino acid 270 disrupts a key topological feature of the DNA – an AT-Hook domain that is a DNA binding motif. By disrupting this domain, the mutation could affect the way the protein bind the DNA and make the already truncated protein much less effective.

"The participation of patients and their families with Rett researchers really helped us to key in on regions of MeCP2 that are critical for its function," said Baker, who is also an M.D./Ph.D. student in BCM's Medical Student Training Program.

The researchers propose a model for this DNA binding in which MeCP2 binds to sites across the genome. In some spots where this occurs, the protein manipulates the structure of the nearby chromatin.

"We think that one function of MeCP2 (the protein associated with the gene) is to alter the architecture of chromatin (the mass of proteins and DNA found in the nucleus of the cell)," said Zoghbi, who is also Howard Hughes Medical Institute investigator.

Baker said, "The picture of MeCP2 as a chromatin architectural factor is emerging from the combined efforts of many laboratories. Understanding how modifies chromatin structure will ultimately allow us to understand why it is so important for neuronal health."

Others who took part in this work include Lin Chen, Angela Dawn Wilkins, Peng Yu and Olivier Lichtarge, all of BCM.

Related Stories

Rett protein MeCP2 needed for proper adult neuron function

Jun 02, 2011

The protein MeCP2 is porridge to the finicky neuron. Like Goldilocks, the neuron or brain cell needs the protein in just the right amount. Girls born with dysfunctional MeCP2 (methyl-CpG-binding protein 2) develop Rett syndrome, ...

Developmental disease is recreated in an adult model

Jun 02, 2011

A new study published today in the journal Science has shown that the childhood disorder Rett syndrome, can be reestablished in adult animals by "switching off" a critical disease causing gene in healthy adult animals. The g ...

Mapping the neuron-behavior link in Rett Syndrome

Sep 24, 2008

A link between certain behaviors and the lack of the protein associated with Rett Syndrome – a devastating autism spectrum disorder – demonstrates the importance of MeCP2 (the protein) and reveals never-before recognized ...

Recommended for you

Science of romantic relationships includes gene factor

Nov 23, 2014

(Medical Xpress)—Adolescents worry about passing tests, winning games, lost phones, fractured bones—and whether or not they will ever really fall in love. Three Chinese researchers have focused on that ...

Stress reaction may be in your dad's DNA, study finds

Nov 21, 2014

Stress in this generation could mean resilience in the next, a new study suggests. Male mice subjected to unpredictable stressors produced offspring that showed more flexible coping strategies when under ...

More genetic clues found in a severe food allergy

Nov 21, 2014

Scientists have identified four new genes associated with the severe food allergy eosinophilic esophagitis (EoE). Because the genes appear to have roles in other allergic diseases and in inflammation, the ...

Brain-dwelling worm in UK man's head sequenced

Nov 20, 2014

For the first time, the genome of a rarely seen tapeworm has been sequenced. The genetic information of this invasive parasite, which lived for four years in a UK resident's brain, offers new opportunities ...

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.