About Rett Syndrome

• Rett Syndrome (RTT) is a severe childhood neurological disorder. The most physically disabling of the autism spectrum disorders, RTT is diagnosed predominantly in girls.


• The disease deprives children of speech, normal movement and hand use. Many children become wheelchair bound; those who walk display an abnormal stiff-legged gait. Disordered breathing patterns and Parkinson-like tremors are common.


• RTT is caused by mutations in a gene called MECP2.

MECP2

• MECP2 was first identified by Adrian Bird, Ph.D. in 1990.


• MECP2 is an epigenetic gene, one of a class of master genes that regulates the expression of other genes, turning them on or off at the appropriate time.


• In 1999 Huda Zoghbi, M.D. discovered that RTT is caused by mutations in MECP2.


• Mutations in MECP2 are now being seen in some cases of childhood schizophrenia, classic autism and learning disabilities.

Study Methodology

• Using a mouse model of RTT, the Bird lab designed an experiment employing technology called Cre-lox to answer the crucial question of whether restoration of normal MECP2 can improve symptoms or even reverse the disorder.


• Cre-lox technology provides a method of locking and then unlocking a gene. Mice were genetically modified to keep MECP2 silenced by inserting a foreign piece of DNA called a lox Stop cassette, thereby creating a model of the deficits seen in RTT. The lox Stop cassette can be spliced out, at will, by using a protein called Cre. Cre is kept anchored to an estrogen receptor in the cytoplasm of the cell while the mice, deprived of functioning MECP2, develop the symptoms of RTT.


• Symptomatic mice were treated with a drug to release the Cre, which migrates to the nucleus and splices out the lox Stop cassette, unlocking MECP2 and allowing it to function normally.

Results

• As MECP2 was gradually restored, Rett symptoms reversed, even in mice who were days away from dying. Breathing, weight, mobility and gait normalized; tremors disappeared.


• Neurophysiological experiments were performed to analyze LTP (long-term potentiation), the quantifiable measurement of the response of brain cells to stimulation. LTP has long been regarded as the cellular basis of learning and memory. Though LTP in RTT mice models is defective, it was restored to normal function by the reversal experiments.

Conclusion

• By establishing the principle of reversibility in mice, the study suggests that RTT and related disorders are also reversible, even in the late stages of the disease.

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