Mutation in mitochondrial chaperone TRAP1 is responsible for male-specific autism

There is growing evidence of mitochondrial disturbance in autism spectrum disorders (ASD) but causative relations remain to be established. We identified postzygotic mozaicp.Q639* mutation in the TRAP1 gene encoding mitochondrial chaperone of the HSP90 family in ASD patient whose monozygotic twin brother was healthy. An additional survey of 176 unrelated ASD probands showed identical TRAP1 variant in a single male patient. We generated a knock-in Trap1 p.Q641*mouse which displayed behavioral abnormalities relevant for ASD, that were more pronounced in males. This effect was corroborated by gender-specific differences in synaptic plasticity and the density of synaptic mitochondria. Next we performed transcriptome profiling by sequencing of RNA isolated from hippocampi of WT, HET and MUT male and female mice