Thread by @rcpsych

This afternoon's #RCPsychIC keynote is by Professor Huda Zoghbi, Professor of Pediatrics, Molecular and Human Genetics, Neurology, and Neuroscience at Baylor College of Medicine (@bcmhouston).

Professor Zoghbi is also an Investigator with the Howard Hughes Medical Institute (@HHMINEWS), and the founding Director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. #RCPsychIC

The talk title of Professor Zoghbi's #RCPsychIC keynote is 'Insight into neuropsychiatric disorders from the study of Rett Syndrome'.

You can find out more about their research here: bcm.edu/research/labs-…

HZ: Rett syndrome is rare with an unusual mix of symptoms.

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HZ: 99.5% of cases are where is just one individual in a family. So this made it harder to find the gene responsible.

The gene is x-linked at the top of the X-chromosome.

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HZ: The MECP2 protein involved is like the 'conductor of an orchestra'.

As it is an X-linked gene, 50% of cells in brain lack protein.

The gene mutation in males occurs where it is severe.

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HZ: Also see hypomorphic mutations which have a phenotype of milder cognitive issues compared to 'Classic Rett'. Mild coding mutations are more penetrant in males.

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HZ: Adding human copy of gene to a mouse model (doubling MeCP2) causes neurological disorders.

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HZ: Majority of female carriers carrying MECP2 duplication display symptoms of depression and/or anxiety.

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HZ: High or low levels of MeCP2 have extreme phenotypes. Triplications of gene are fatal.
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HZ: Used a sequencing approach called 'ATAC-seq' to reveal candidate regulatory elements of the MeCP2 gene. Many such elements are in the non-coding introns of the gene.

Tried systematic deletion of elements.

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HZ: Deletion of some of these elements led to changes in levels of MECP2 protein. Can increase or decrease expression based on which element is deleted.

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HZ: Mutations in these two regions in humans might not manifest as Rett syndrome but as other neuropsychiatric phenotypes.

Important to sequence these regions in patients with psychiatric disorders.

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HZ: Hypothesis that physical training could help improve Rett phenotypes. In mice investigated frequency and timing of early training (using rotarod performance).
Early training helps.
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HZ: Training before onset of symptoms helped memory acquisition.
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HZ: Repetitive training improves neuronal morphology of some neurons. This has clinical implications for humans.

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Professor Huda Zoghbi now concluding her keynote talk and giving a special thanks to all the families who have contributed to this research.

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