Molecular consequences of strong-effect autism mutations, including 16p11.2

  • Awarded: 2014
  • Award Type: Research
  • Award #: 308955

Understanding how genetic defects that cause autism lead to abnormal neurodevelopment is critical to developing mechanism-based treatments. One particularly important question is whether different genetic defects produce autism traits in completely different ways, or whether alterations in different genes trigger a cascade of cellular changes that overlap and ultimately lead to autism by the same biochemical mechanism. James Gusella and his colleagues at Massachusetts General Hospital aim to explore this question by using cutting-edge genome modification techniques to compare the effects of different autism-linked genetic traits in cultured human stem cells and neurons.

In a small-scale preliminary study using interference with messenger RNA, Gusella and his group suppressed expression of several autism genes whose normal function is to help regulate the timing and level of expression of other genes throughout the human genome1. The results indicated that reducing the expression of some autism genes in neuronal progenitor cells alters the expression of many other autism genes.

To better define the gene networks involved in autism, the researchers are now applying a new genome editing technique that introduces precise mutations into selected autism genes in human stem cells, and are then measuring genome-wide expression changes. These comparisons are being done in authentic human cells with identical genomes (other than the introduced mutation) at the neural progenitor stage and throughout their development into mature nerve cells, a process of fundamental relevance to neurodevelopment in autism.

The results of this analysis will test the hypothesis that different autism genes produce the disorder by leading to the same kinds of changes in nerve cell development and that this biochemical mechanism is also triggered by the common deletion mutation of chromosomal region 16p11.2. Identification of a shared disease process despite different initial triggering genes would allow researchers to target that shared process for the development of interventions that would apply broadly in autism.

 

References

1.Sugathan A. et al. Proc. Natl. Acad. Sci. USA 111, E4468-4477 (2014) PubMed
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