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

• Published in: EMBO molecular medicine Vol. 16; no. 11; pp. 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: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-09-2024; Springer Nature
• Subjects: Autism; Biomedical and Life Sciences; Biomedicine; EMBO16; EMBO57; Mitochondria; Molecular Medicine; Mouse Model; Synapses; Trap1; Trap1; Autism; Mitochondria; Synapses; Mouse Model
• 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.