Rydzanicz 2024 EMBO Mol Med

Rydzanicz M, Kuzniewska B, Magnowska M, Wójtowicz T, Stawikowska A, Hojka A, Borsuk E, Meyza K, Gewartowska O, Gruchota J, Miłek J, Wardaszka P, Chojnicka I, Kondrakiewicz L, Dymkowska D, Puścian A, Knapska E, Dziembowski A, Płoski R, Dziembowska M (2024) Mutation in the mitochondrial chaperone TRAP1 leads to autism with more severe symptoms in males. EMBO Mol Med [Epub ahead of print]. https://doi.org/10.1038/s44321-024-00147-6

» PMID: 39333440 Open Access

Rydzanicz Malgorzata, Kuzniewska Bozena, Magnowska Marta, Wojtowicz Tomasz, Stawikowska Aleksandra, Hojka Anna, Borsuk Ewa, Meyza Ksenia, Gewartowska Olga, Gruchota Jakub, Milek Jacek, Wardaszka Patrycja, Chojnicka Izabela, Kondrakiewicz Ludwika, Dymkowska Dorota, Puscian Alicja, Knapska Ewelina, Dziembowski Andrzej, Ploski Rafal, Dziembowska Magdalena (2024) EMBO Mol Med

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. • Keywords: Autism, Mitochondria, Mouse Model, Synapses Trap1 • Bioblast editor: Plangger M • O2k-Network Lab: PL Warsaw Zablocki K

Labels: MiParea: Respiration, nDNA;cell genetics  Pathology: Autism 

Organism: Mouse  Tissue;cell: Nervous system  Preparation: Isolated mitochondria 

Coupling state: ET, LEAK  Pathway: N, S, CIV  HRR: Oxygraph-2k 

2024-10