Rydzanicz et al., 2024 reported a postzygotic mosaic nonsense variant in the TRAP1 gene (p.Gln639Ter) in an ASD proband from an ASD-discordant monozygotic twin pair; additional screening of 176 unrelated Polish ASD probands identified the same TRAP1 variant in a male patient who had inherited it from a healthy mother. Knock-in mice with the equivalent p.Gln641Ter mutation displayed ASD-related behavioral abnormalities that were more pronounced in males than in females, and this mutation also resulted in sex-specific changes in synaptic plasticity, the number of presynaptic mitochondria, and mitochondrial respiration. Inherited loss-of-function variants in the TRAP1 gene have previously been observed in individuals with ASD from four multiplex families from the AGRE cohort (Cirnigliaro et al., 2023).
Molecular Function
This gene encodes a mitochondrial chaperone protein that is member of the heat shock protein 90 (HSP90) family. The encoded protein has ATPase activity and interacts with tumor necrosis factor type I. This protein may function in regulating cellular stress responses.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Mutation in the mitochondrial chaperone TRAP1 leads to autism with more severe symptoms in males
The homozygous and heterozygous mutant Trap1 mouse models with a nonsense mutation found in humans (Q639X) are viable and fertile. Male but not female mutants show in-cohort sociability deficits, and all mutants show deficits in social approach with a novel stimulus mouse.
References
Type
Title
Author, Year
Primary
Mutation in the mitochondrial chaperone TRAP1 leads to autism with more severe symptoms in males
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Homozygous knockin mice carry two alleles with a Q641X nonsense mutation in the Trap1 gene.
Allele Type: ASD mutation
Strain of Origin: CBA
Genetic Background: C57BL/6
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: Mouse Genome Engineering Facility (www.crisprmice.eu)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Heterozygous knockin mice carry one allele with a Q641X nonsense mutation in the Trap1 gene.
Allele Type: ASD mutation
Strain of Origin: CBA
Genetic Background: C57BL/6
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: Mouse Genome Engineering Facility (www.crisprmice.eu)
Description: Male homozygous mice displayed increased spine density in hippocampus, slightly decreased in the amygdala and no change in the medial prefrontal cortex. Female homozygous mutants show slightly reduced spine density in hippocampus, increased in medial prefrontal cortex, no change in amygdala.
Exp Paradigm: DiI staining
Description: Male homozygous mutants have spines that are shorter and had decreased area, in the hippocampus, but no change in medial prefrontal cortex or amygdala.
Exp Paradigm: DiI staining
Description: Female homozygous mutants have larger individual spines in the hippocampus and medial prefrontal cortex but no change in the amygdala.
Exp Paradigm: DiI staining
Description: AMPAR-mediated synaptic signals were significantly more pronounced in the hippocampus of male homozygous mice. Male homozygous mice exhibited significantly larger NMDARs-mediated synaptic responses compared to wildtype littermates.
Description: Female heterozygous mutants have larger spine size in the medial prefrontal cortex but show no change in the hippocampus or amygdala.
Exp Paradigm: DiI staining
Description: Male and female homozygous mutants show increased spine density in the medial prefrontal cortex but no change in hippocampus or amygdala.
Exp Paradigm: DiI staining
