Genetics: Study finds risk gene for autism in males
Because men have only one copy of the X chromosome, mutations in X chromosome genes have a more severe effect on men than they do on women. Researchers have speculated that rare variants in X chromosome genes could explain why autism is more common in men than in women.
A mutation that silences expression of the AFF2 gene leads to a rare disorder, called fragile X E intellectual disability, that is often accompanied by autism.
In the new study, researchers sequenced AFF2 in 202 men with autism — 127 from the Autism Genetic Resource Exchange, and the other 75 from the Simons Simplex Collection, which is funded by SFARI.org’s parent organization.
In five of the men, the researchers found five different rare mutations in AFF2 that disrupt the protein sequence and so are likely to be harmful. In contrast, only 33 of 5,545 controls have a harmful mutation in the gene.
The five mutations alter amino acids conserved across several species, including monkeys, mice and dogs. This further suggests that disrupting these amino acids is likely to alter the structure of the protein.
Four of the five men inherited the mutation from their unaffected mothers, who have one X chromosome with the variant and one with the typical amino acid. The fifth man has a spontaneous mutation. Of the four who inherited the variant, two share the variant with a brother who also has autism, the third has an unaffected brother who does not have the mutation and the fourth has an unaffected brother who has not yet been tested for the mutation.
The researchers also identified two variants in a regulatory region known to influence the gene’s expression. The variants lower AFF2 expression in human embryonic kidney cells and elevate it in mouse neurons, suggesting that their influence may be tissue specific, the researchers say.
1: Mondal K. et al. Hum. Mol. Genet. Epub ahead of print (2012) PubMed