Finding the Rett syndrome gene and ways to fix it

In the mid-1980s, Huda Zoghbi encountered her first patient with Rett syndrome during her residency in genetics clinic in Texas. This encounter ignited her passion to comprehend the underlying genetic cause of this debilitating condition. Rett syndrome, predominantly affecting girls, is characterized by symptoms like autism, neurological issues, reduced motor coordination, and the onset of regression around 2 years of age.

The disorder results from mutations in the MECP2 gene, which is found on the X chromosome and encodes a protein that regulates gene expression by binding to methylated DNA.

In 1999, a decade after her initial encounter, Zoghbi and her team successfully identified the MECP2 gene. Through their research, they discovered that the gene is essential during brain development but also plays a crucial role in synaptic development and plasticity later in life. Knocking out the gene in mice led to the manifestation of many Rett syndrome symptoms, and restoring the gene in adulthood could reverse these symptoms.

Interestingly, increasing the level of MECP2 protein also causes neurological issues in mice, a phenomenon also seen in humans with MECP2 duplications.

Zoghbi's work on Rett syndrome has broader implications for autism research, as many genes involved in Rett syndrome are also implicated in autism. This highlights the interconnectedness of systems that regulate gene expression and synaptic function, which are critical for learning and information maintenance. Zoghbi and her colleagues have explored various therapeutic approaches for Rett syndrome, including deep brain stimulation, intensive behavioral interventions, and molecular therapeutics like antisense oligonucleotides.

These advancements hold promise for improving the lives of individuals affected by Rett syndrome and their families, nearly 40 years after Zoghbi first met a patient with the condition.