Recessive autism genes
While the search for common variants that increase risk for autism has not been very fruitful, the identification of rare, often de novo, changes that lead to autism has met with more success. Now, Christopher Walsh and colleagues report the results of their effort to identify recessive genes for autism risk (Science 321, 218–223; 2008). The authors used a collection of 88 autism families with parental consanguinity. Homozygosity mapping in these families revealed several potentially linked loci that were mostly family-specific. Interestingly, some of the linked loci contained large inherited deletions. One deletion in a child with autism and seizures removed an uncharacterized gene the authors named DIA1 (deleted in autism1) and was near the 5′ end of the NHE9 gene, which encodes a (Na+,K+)/H+ exchanger. The authors identified a heterozygous nonsense mutation in NHE9 in a non-consanguineous autism family with epilepsy or seizures, and they found an excess of rare, nonconservative coding changes in NHE9 in autism cases with epilepsy compared to controls. NHE9 and DIA1 were both identified in screens for genes regulated by neuronal activity in rat hippocampal neurons. This study identifies good candidates for future studies, and it also implicates neuronal activity–dependent regulation of gene expression as a potential pathogenic mechanism underlying the autism phenotype. EN
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