, FK228 order 2002). A targeted Rims1 mutation in the mouse leads to increased postsynaptic density and impaired associative learning as well as memory and cognition deficits ( Powell et al., 2004 and Schoch et al., 2002), and the frame shift allele

we found may lead to a similarly severe condition. Another intriguing candidate was the serine/threonine-specific protein kinase DYRK1A, which is located within the Down syndrome critical region of chromosome 21 and believed to underlie at least some of the pathogenesis of Down syndrome as a consequence of increased dosage. Several reports of likely inactivating mutations in DYRK1A result in symptoms including developmental delay, behavioral problems, impaired speech and mental retardation ( Møller et al., 2008 and van Bon et al., 2011), and a heterozygous knockout in the mouse also led to developmental this website delay and increased neuronal densities ( Fotaki et al., 2002). Truncating mutations in ZFYVE26 (encoding a zinc finger protein) are known to cause autosomal recessive spastic paraplegia-15,

consisting of lower limb spasticity, cognitive deterioration, axonal neuropathy and white matter abnormalities ( Hanein et al., 2008). It is possible that a heterozygous truncating mutation such as the de novo frame shift allele found in our study might cause a less severe version of this condition resulting in an ASD diagnosis. Other de novo mutations of interest were a 4 bp deletion in DST (encoding the basement membrane glycoprotein dystonin), which is associated with FMRP ( Darnell et al., 2011) and produces a neurodegeneration phenotype when inactivated in the mouse, and a nonsense mutation in ANK2 (an ankyrin protein involved in synaptic stability [ Koch et al., 2008]). A nonsense mutation in UNC80 has been linked next to control of “slow” neuronal excitability ( Lu et al., 2010). We also note that thirteen of the 59 LGD candidates appear to be involved in either transcription regulation or chromatin remodeling. Among the latter are three proteins involved in epigenetic

modification of histones: ASH1L, a histone H3/H4 methyltransferase that activates transcription (Gregory et al., 2007); KDM6B, a histone H3 demethylase implicated in multiple developmental processes (Swigut and Wysocka, 2007), and MLL5, a histone H3 methyltranserase involved in cell lineage determination (Fujiki et al., 2009). These three are also FMRP-associated genes. Fragile X syndrome (FXS) is one of the most common genetic causes of intellectual disability, with up to 90% of affected children exhibiting autistic symptoms. This has suggested overlaying recent understanding of FXS biology onto candidate ASD genes (Darnell et al., 2011). The FMR1 gene is expressed in neurons and controls the translation of many products.