Huda Zoghbi encountered her first patient with Rett syndrome as a medical resident at a genetics clinic in Texas in the 1980s. The meeting had a profound personal impact, setting Zoghbi on her professional course to try to understand the basis of this devastating genetic condition. Rett syndrome, which results in autism and neurological problems, including hypotonia, seizures and reduced motor coordination, almost exclusively affects girls, and its course is starkly regressive. Symptoms first appear at about 2 years of age, when previously typically developing girls lose language and motor skills, stop making eye contact, become withdrawn and develop repetitive behaviors, such as hand-wringing.
In 1999, more than a decade after that first meeting, Zoghbi and her collaborators identified the MECP2 gene, which resides on the X chromosome and encodes a protein that binds to methylated DNA and regulates gene expression. Rett syndrome affects primarily girls because boys who inherit MECP2 variants show much more severe symptoms, often dying in early infancy.
In this interview, I talk with Zoghbi, now professor of molecular and human genetics, neuroscience and pediatric neurology at Baylor College of Medicine, about that discovery and her efforts in the decades that followed studying mouse models to try to figure out how variants in this gene lead to Rett traits. Zoghbi and her colleagues showed that knocking out the gene completely in mice affects the expression of hundreds of genes and recapitulates many of the phenotypes seen in people with Rett syndrome. By knocking it out only in certain brain areas or cell types, they have been able to link different circuits and systems to different symptoms of the syndrome. One of their most striking findings is that the gene is not just required during brain development, as one might expect for a classic “neurodevelopmental disorder.” Removing it only in adulthood—after typical neural development—results in the same set of phenotypes in mice missing the gene since birth. And, remarkably, the symptoms of knockout mice can be rescued by restoring the gene in adults.
Eventually, work from Zoghbi and others revealed that Rett syndrome is really a disorder of postnatal synaptic development and plasticity. MECP2 seems to be a key hub protein involved in coordinating gene expression in response to neuronal activity, helping to maintain synaptic weights across neuronal networks in a dynamic range. In our conversation, we discuss why these processes become so important around 2 years of age, which may reflect the pace of postnatal pruning of synaptic connections, as well as increasing cognitive demands.
We also discuss why these processes are so sensitive to the dosage of MECP2. One of Zoghbi’s most remarkable discoveries—made while generating transgenic mice carrying what was intended to be a “rescue construct” of MECP2—is that increasing the dose of MECP2 also causes a neurological condition. This condition has subsequently been observed in people who carry a duplication of the MECP2 gene. It turns out that altering the amount of the MECP2 protein by as little as 30 percent can have pathological consequences.
The study of Rett syndrome has important implications for autism more broadly. Many other chromatin-regulating genes, as well as genes involved in synapse development and plasticity, have been implicated in this condition. There thus seems to be some convergence onto a system that sensitively links ongoing control of gene expression to mechanisms of network homeostasis required for learning and maintaining different kinds of information. Subtle disruptions to these systems can result in autism, and more severe disruptions lead to wider cognitive and neurological impairments.
Zoghbi has also helped to develop several therapeutic approaches for people with Rett syndrome. The first of these is deep brain stimulation, which can counter defects in neurons in specific brain areas in mice. A second approach involves intensive behavioral interventions at early stages, which show promise in preventing future regression of some abilities, in some way rendering them independent of later MECP2 function. And a third involves molecular therapeutics, such as antisense oligonucleotides, now in clinical trials to treat boys with MECP2 duplication syndrome.
Decades after her first encounter with someone with Rett syndrome, Zoghbi’s persistence and discovery has led to the very real promise of improving the lives of the people and families it affects.
Watch the video and read the transcript.
