Closer to the Genetic Roots of Autism

To go with this past Friday’s post on Alzheimer’s, recent progress is being made in understanding Autism. That’s the claim coming from an initial identification of a gene called CNTNAP2, which when mutated, this gene indicated a predisposition to autism in a specific population of Old Order Amish children from Pennsylvania. Three separate studies recently confirmed that mutation of this gene correlates with Type-I Autism, and are published in the American Journal of Human Genetics.

Dietrich A. Stephan, whose group made the initial discovery¹ wrote the commentary in AJHG: Unraveling Autism².

the contactin associated protein-like 2 (CNTNAP2) gene at 7q35, a member of the neurexin superfamily, was described by our group in 2006 to cause severe autism with medication-insensitive temporal lobe seizures, language regression, and low IQ when the carboxy terminal of the protein product was truncated through a homozygous loss-of-function mutation in a single family. The mechanism of action of the mutation is likely altered attachment of the axon to the glia via the TAG-1 protein and mislocalization of ion channels at the juxtaparanodal junction leading to cortical dysplasia. This finding is now replicated in a large sampling of the autism population by three groups in this issue of AJHG and places the CNTNAP2 gene as the first widely replicated autism-predisposition gene.

The next step, as Stephan notes, is to develop assays for mutations in CNTNAP2 as diagnostic and prognostic tools. A host of other questions will have to be unraveled with further research as well. But, in the Amish study¹, the gene was observed to be recessive - and thus potentially amenable to gene therapy, if obstacles to gene therapy can be overcome.

What’s interesting is that I had thought that the various forms of autism were the result of several, perhaps many, genes acting synergistically to generate a phenotype somewhere along the spectrum of autistic disorders, or by copy-number variations of genes. For instance, only about 10-15% of autism cases display patterns of Mendelian (single-gene) inheritance, chromosome abnormality, or other genetic syndrome.

1. Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM, Stephan DA, Morton DH. (2006) N. Engl. J. Med., 354, 1370–1377. PubMed
2. Stephan DA. (2008) Unraveling Autism. Am. J. Hum. Genet., 82, 7-9. 10.1016/j.ajhg.2007.12.003

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