1. Alvarez Retuerto AI, Cantor RM, Gleeson JG, Ustaszewska A, Schackwitz WS, Pennacchio LA, Geschwind DH. {{Association of common variants in the Joubert syndrome gene (AHI1) with autism}}. {Hum Mol Genet};2008 (Dec 15);17(24):3887-3896.

It has been suggested that autism, like other complex genetic disorders, may benefit from the study of rare or Mendelian variants associated with syndromic or non-syndromic forms of the disease. However, there are few examples in which common variation in genes causing a Mendelian neuropsychiatric disorder has been shown to contribute to disease susceptibility in an allied common condition. Joubert syndrome (JS) is a rare recessively inherited disorder, with mutations reported at several loci including the gene Abelson’s Helper Integration 1 (AHI1). A significant proportion of patients with JS, in some studies up to 40%, have been diagnosed with autism spectrum disorder (ASD) and several linkage studies in ASD have nominally implicated the region on 6q where AHI1 resides. To evaluate AHI1 in ASD, we performed a three-stage analysis of AHI1 as an a priori candidate gene for autism. Re-sequencing was first used to screen AHI1, followed by two subsequent association studies, one limited and one covering the gene more completely, in Autism Genetic Resource Exchange (AGRE) families. In stage 3, we found evidence of an associated haplotype in AHI1 with ASD after correction for multiple comparisons, in a region of the gene that had been previously associated with schizophrenia. These data suggest a role for AHI1 in common disorders affecting human cognition and behavior.

2. Piton A, Michaud JL, Peng H, Aradhya S, Gauthier J, Mottron L, Champagne N, Lafreniere RG, Hamdan FF, Joober R, Fombonne E, Marineau C, Cossette P, Dube MP, Haghighi P, Drapeau P, Barker PA, Carbonetto S, Rouleau GA. {{Mutations in the calcium-related gene IL1RAPL1 are associated with autism}}. {Hum Mol Genet};2008 (Dec 15);17(24):3965-3974.S2D team

In a systematic sequencing screen of synaptic genes on the X chromosome, we have identified an autistic female without mental retardation (MR) who carries a de novo frameshift Ile367SerfsX6 mutation in Interleukin-1 Receptor Accessory Protein-Like 1 (IL1RAPL1), a gene implicated in calcium-regulated vesicle release and dendrite differentiation. We showed that the function of the resulting truncated IL1RAPL1 protein is severely altered in hippocampal neurons, by measuring its effect on neurite outgrowth activity. We also sequenced the coding region of the close related member IL1RAPL2 and of NCS-1/FREQ, which physically interacts with IL1RAPL1, in a cohort of subjects with autism. The screening failed to identify non-synonymous variant in IL1RAPL2, whereas a rare missense (R102Q) in NCS-1/FREQ was identified in one autistic patient. Furthermore, we identified by comparative genomic hybridization a large intragenic deletion of exons 3-7 of IL1RAPL1 in three brothers with autism and/or MR. This deletion causes a frameshift and the introduction of a premature stop codon, Ala28GlufsX15, at the very beginning of the protein. All together, our results indicate that mutations in IL1RAPL1 cause a spectrum of neurological impairments ranging from MR to high functioning autism.

3. Vojdani A, Mumper E, Granpeesheh D, Mielke L, Traver D, Bock K, Hirani K, Neubrander J, Woeller KN, O’Hara N, Usman A, Schneider C, Hebroni F, Berookhim J, McCandless J. {{Low natural killer cell cytotoxic activity in autism: The role of glutathione, IL-2 and IL-15}}. J {Neuroimmunol};2008 (Dec 15);205(1-2):148-154.

Although many articles have reported immune abnormalities in autism, NK cell activity has only been examined in one study of 31 patients, of whom 12 were found to have reduced NK activity. The mechanism behind this low NK cell activity was not explored. For this reason, we explored the measurement of NK cell activity in 1027 blood samples from autistic children obtained from ten clinics and compared the results to 113 healthy controls. This counting of NK cells and the measurement of their lytic activity enabled us to express the NK cell activity/100 cells. At the cutoff of 15-50 LU we found that NK cell activity was low in 41-81% of the patients from the different clinics. This NK cell activity below 15 LU was found in only 8% of healthy subjects (p<0.001). Low NK cell activity in both groups did not correlate with percentage and absolute number of CD16(+)/CD56(+) cells. When the NK cytotoxic activity was expressed based on activity/100 CD16(+)/CD56(+) cells, several patients who had displayed NK cell activity below 15 LU exhibited normal NK cell activity. Overall, after this correction factor, 45% of the children with autism still exhibited low NK cell activity, correlating with the intracellular level of glutathione. Finally, we cultured lymphocytes of patients with low or high NK cell activity/cell with or without glutathione, IL-2 and IL-15. The induction of NK cell activity by IL-2, IL-15 and glutathione was more pronounced in a subgroup with very low NK cell activity. We conclude that that 45% of a subgroup of children with autism suffers from low NK cell activity, and that low intracellular levels of glutathione, IL-2 and IL-15 may be responsible.