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

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.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2024-09-27
DOI
https://doi.org/10.1038/s44321-024-00147-6
Citations
8
Primary Topic
Genetics and Neurodevelopmental Disorders
Type
article
Field-Weighted Citation Impact
3.85

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article

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

Olga Gewartowska, Ewa Borsuk, Magdalena Dziembowska, Marta Magnowska et al.
8 citations
EMBO Molecular Medicine
Genetics and Neurodevelopmental Disorders
3.85
article

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

Olga Gewartowska, Ewa Borsuk, Magdalena Dziembowska, Marta Magnowska, Dorota Dymkowska, Bożena Kuźniewska, Rafał Płoski, Alicja Puścian, Ludwika Kondrakiewicz, Izabela Chojnicka, Patrycja Wardaszka, Małgorzata Rydzanicz, Jacek Miłek, Tomasz Wójtowicz, Jakub Gruchota, Ksenia Meyza, Andrzej Dziembowski, Ewelina Knapska, Aleksandra Stawikowska, Anna Hojka
article en
8 citations

Abstract

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.

EMBO Molecular MedicineVol. 16(11)
Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL), Medical University of Warsaw (PL), International Institute of Molecular and Cell Biology (PL), University of Warsaw (PL)
European Commission, Fundacja na rzecz Nauki Polskiej, Narodowe Centrum Nauki, Instytut Biologii Doswiadczalnej im. M. Nenckiego PAN, Międzynarodowy Instytut Biologii Molekularnej i Komórkowej w Warszawie
Good health and well-being
Openalex Percentile: Top 6%
Genetics and Neurodevelopmental Disorders
3.85
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