Mutation in the mitochondrial chaperone TRAP1 leads to autism with more severe symptoms in males

• Published in: EMBO molecular medicine 2024-11, Vol.16 (11), p.2976-3004
• Main Authors: Rydzanicz, Małgorzata, Kuzniewska, Bozena, Magnowska, Marta, Wójtowicz, Tomasz, Stawikowska, Aleksandra, Hojka, Anna, Borsuk, Ewa, Meyza, Ksenia, Gewartowska, Olga, Gruchota, Jakub, Miłek, Jacek, Wardaszka, Patrycja, Chojnicka, Izabela, Kondrakiewicz, Ludwika, Dymkowska, Dorota, Puścian, Alicja, Knapska, Ewelina, Dziembowski, Andrzej, Płoski, Rafał, Dziembowska, Magdalena
• Format: Article
• Language: English
• Subjects: Animals; Autism; Autism Spectrum Disorder - genetics; Autistic Disorder - genetics; Biomedical and Life Sciences; Biomedicine; EMBO16; EMBO57; Female; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Humans; Male; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Molecular Medicine; Mouse Model; Mutation; Pedigree; Sex Factors; Synapses; Trap1
• ISSN: 1757-4684; 1757-4676; 1757-4684
• DOI: 10.1038/s44321-024-00147-6

There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-in Trap1 p.Q641* mice display ASD-related behavioral abnormalities that are more pronounced in males than in females. Accordingly, Trap1 p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, the number of presynaptic mitochondria, and mitochondrial respiration. Thus, the TRAP1 p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis. Synopsis Evidence suggests mitochondrial homeostasis plays a role in autism spectrum disorders (ASDs), but the causal relationships remain unclear. In the new model of the first monogenic ASD caused by mutation in mitochondrial chaperone, TRAP1 mutant mice display ASD-related phenotypes that are more pronounced in males than in females. A novel TRAP1 p.Q639* mutation in mitochondrial chaperonin identified in ASD-diagnosed monozygotic twin brother and another unrelated ASD patient. Knock-in Trap1 p.Q641* mice display social deficits, more pronounced in males. Sex-specific changes in dendritic spine density, morphology and basal synaptic transmission are observed in Trap1 p.Q641* mice. Decreased number of presynaptic mitochondria and changes in mitochondrial metabolism are detected in Trap1 p.Q641* mice. Evidence suggests mitochondrial homeostasis plays a role in autism spectrum disorders (ASDs), but the causal relationships remain unclear. In the new model of the first monogenic ASD caused by mutation in mitochondrial chaperone, TRAP1 mutant mice display ASD-related phenotypes that are more pronounced in males than in females.