, 2011). Hence, we checked the list of FMRP-associated genes with our lists of 59 LGD targets

and 72 most likely autism candidate genes from de novo CNVs, and found a remarkable overlap: Selleckchem Galunisertib 14 and 13 with one in common, thus 26/129, with a p value of 10−13 determined on a per gene basis (842 FMRP-associated genes out of 25,000 genes). This overlap is remarkable because half of the LGD targets should not be ASD related, and probably a similar number of the most likely CNV genes. We found no unusual overlap between the FMRP-associated genes and de novo LGD targets in unaffected siblings, or between FMRP-associated genes and de novo missense targets in either affected or unaffected children. As a follow-up to this striking observation, we searched for de novo mutations in targets upstream of FMR1 and found an intriguing

one: GRM5. It is hit by a deletion that is not a frame shift but removes a single amino acid and causes an additional substitution at the deletion site. GRM5 encodes mGluR5, a glutamate receptor coupled to a G protein ( Bear et al., 2004). Defects in mGluR5 compensate for some of the fragile X symptoms in mice ( Dölen et al., 2007), and mGluR5 antagonists are currently in clinical trial ( Jacquemont et al., 2011). FMRP has been proposed to inhibit protein translation of certain critical transcripts involved in neuroplasticity, the coordinated sensitization or desensitization of neurons in response to activity. Hence, it is reasonable to

CP 868596 suppose that the physiological mechanisms modulated by FMRP depend on protein concentration, which in turn might be sensitive to gene dosage. Direct support for this idea comes from surveying the entire parental population for carriers of potentially disruptive gene variants. Using a well-annotated set of human genes as controls, FMRP-associated genes are strongly depleted for mutations that affect splicing or introduce stop codons. The statistical significance of the numbers is striking, whether computed as a rate relative to synonymous mutations or on MRIP a per gene basis. We see a similar depletion of LGDs in a set of human orthologs of mouse genes that are enriched for essential genes but we do not see this extreme depletion in a set of 250 genes linked to known disabling genetic disorders. This difference may reflect the strong purifying selection in humans against disruptions of even a single allele of genes in this set. The hypothesis that the majority of the FMRP-associated genes are dosage-sensitive requires a more thorough analysis. FMRP may act as one component of a central regulator of synaptic plasticity, among others such as TSC2 (Darnell et al., 2011 and Auerbach et al., 2011). Impairment of its function, or the components it regulates, or other regulators like it, might produce a deficit in human adaptive responses. This study shows these components may be dosage-sensitive targets in autism.