Proteins that guide placement of neurons linked to autism and ADHD

March 4, 2014

Genetic evidence is increasingly pointing to similarities between neurodevelopmental disorders on a molecular level. In a recent paper NeuroDevNet trainee Anath Lionel, a PhD candidate based in Dr. Stephen Scherer’s lab, and co-authors added detail to this picture with an exploration of mutations in a gens that encodes a protein that helps direct where neurons settle in the developing brain.

 In their examination of duplications and deletions in ASTN2 in more than 90,000 people referred for genetic microarray testing, Lionel and colleagues found mutations known as Copy Number Variations, or CNVs, that may be risk factors for autism and ADHD.

“We found 58 CNVs (46 deletions and 12 duplications) in ASTN2,” says Lionel. “These CNVs are four times more likely to present in people with neurodevelopmental disorders (NDDs) than in controls,” he adds, noting that 64,000 of the people represented in the study cohort already carried an NDD diagnosis.

The paper, entitled “Disruption of the ASTN2 /TRIM32 locus gene region on at chromosome 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes,” was published January 14 in Human Molecular Genetics.

“One of the biggest puzzles in ASD and ADHD is why the gender balance is so different,” says Lionel.

The physiology of males somehow leaves them poised to cross the threshold towards autism more easily than girls, adds Dr. Scherer, Director of The Centre for Applied Genomics at SickKids Hospital and the McLaughlin Centre at the University of Toronto.

CNVs that disrupt the end of the ASTN2 gene, which regulates variants of the protein are also three times more common in males than in females with neurodevelopmental disorders but show no gender bias in controls.

“I think there are short and longer-term implications to these findings,” says Lionel. “In the short term, we see genes that keep being implicated in NDDs, but not in controls, that indicate NDDs are related at a molecular level."

In the longer term, increased understanding of the pathways of NDDs, and the shift to whole genome sequencing in diagnostics will help push development of highly targeted drugs and interventions, says Lionel. Identifying genes associated with key processes in brain development and their associations with specific disorders is where the promise lies in terms of developing real help for affected individuals, he adds.

"Each month we understand a little bit more about the factors involved in autism and with this knowledge new ideas are emerging of how enable earlier diagnosis and individualized medicines for individuals and families in need”, says Dr. Scherer.

Figure:  Expression profiles of ASTN2 across human brain development. The gene level expression profiles of  ASTN2 across developmental time points in nine regions of the human brain; amygdala (AMY), cerebellar cortex (CBC), diencephalon (DIE), frontal cortex (FC), hippocampus (HIP), occipital cortex (OC), parietal cortex (PC), temporal cortex (TC) and ventral forebrain (VF).