Key Piece of Genetic Autism Puzzle Discovered

Boys shows signs of autism spectrum disorders more often than girls. But, autism is strongly hereditary. What's going on? The most parsimonious assumption is that there are one or more X chromosome linked genes that are protective against problems created by autism causing genes elsewhere in the genome.

The DIA1R gene (which stands for "deleted in autism one related" because it influeces the expression of the autosomal DIA1 gene on chromosome 3 which is "deleted in autism") seems to fit the bill:

[M]utations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. . . . [DIA1 and DIA1R synthesize two very similar] signal peptides for targeting to the secretory pathway [probably for the same system in the brain]. Both genes are ubiquitously expressed, including in fetal and adult brain tissue.

Another similar X linked gene with the same kind of protective role that was previously discovered was DDX53-PTCHD1.

Since girls have two X chromosomes and since one protective gene seems to provide at least some benefit even if that girl also has a deleted DIA1R gene, girls are more likely to have some protection from their deleterious autism related genes. But, a boy with a deleted DIA1R gene in his one X chromsome lacks to XLMR/autism spectrum disorder protective trait and shows more autism spectrum disorder or retardation symptoms. A girl with some, but not all of the protective X linked genes, may sometimes not be symptom free but may still experience a milder autism spectrum disorder (e.g. Asperger's) than a boy who lacks more of these protective genes.

Since this basic genetic model involving autosomal autism causing traits that frequently arise by novel mutation and X linked protective genes was proposed in 2007, scientists have identified at least the two key X linked protective genes described above and have gained some insight into what at least one of them does. Researchers have also in the last three and a half years, increasingly come to conclude that there is not a single primary autism causing gene, although all of the known autism causing genes do appear to be dominant rather than recessive in effect.

Researchers also know that the gene DIA1, and probably other genes appear to contribute to autism, but that there also appear to be a whole host of other autism causing mutations. About two-thirds of these arise from new mutations in sperm cells that are not present in the parent, while the other third are inherited from a less symtomatic mother or a mildly symptomatic father, or both.

The brain chemistry system that genes like DIA1R and DDX53-PTCHD1 protect is apparently highly prone to malfunction from a large number of other genes, none of which is predominant as a cause of autism, perhaps because the process impacted is intricate and delicate, without these protective genes. But, we actually have only a dim idea of precisely which process or processes in the brain that autism disrupts, and in general. We know what happens when this process, whatever it is, goes wrong, in great detail, but not why a problem with this process causes this effect. This is, of course, unfortunate, since it is hard to treat autism in people who have it already until we have a better idea of what is broken that causes these symptoms. But, the more we can pin down the genes produce autism spectrum disorders, the more we can engage in a narrow and targeted effort to understand how this process in the brain works and what these genes do to disrupt its normal functioning.