ArticleHuman molecular genetics2020
De novo mutations in TOMM70, a receptor of the mitochondrial import translocase, cause neurological impairment.
Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 27 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network
Who cites it
27 citing papers in PubMed, 40 citations in OpenAlex.
- From the cytosol to the inner membrane: biogenesis of the mitochondrial carrier family.Protein science : a publication of the Protein Society · 2026Review
- De novo and inherited variants in DDX39B cause a novel neurodevelopmental syndrome.Brain : a journal of neurology · 2025Article
- Functional assays inGenome research · 2025Review
- Patient-specific mutation of contact site protein Tomm70 causes neurodegeneration.Disease models & mechanisms · 2025Article
- Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.EBioMedicine · 2024Article
- Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5.Frontiers of medicine · 2024Article
- Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans.Nature reviews. Genetics · 2024Review
- Mitohormesis.Cell metabolism · 2023Review
- A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.Nature metabolism · 2023Article
- A comprehensive Drosophila resource to identify key functional interactions between SARS-CoV-2 factors and host proteins.Cell reports · 2023Article
- Article
- Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development.Cerebellum (London, England) · 2023Article
- Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy.American journal of human genetics · 2023Article
- Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.The Journal of clinical investigation · 2022Article
- Mitochondrial biology and dysfunction in secondary mitochondrial disease.Open biology · 2022Review
- Whole Exome Sequencing in Patients With Ectopic Posterior Pituitary.Journal of the Endocrine Society · 2022Article
- Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures.American journal of human genetics · 2022Article
- Invertebrate Model Organisms as a Platform to Investigate Rare Human Neurological Diseases.Experimental neurobiology · 2022Review
- Inter-Species Rescue of Mutant Phenotype-The Standard for Genetic Analysis of Human Genetic Disorders inInternational journal of molecular sciences · 2022Review
- Mitochondrial protein dysfunction in pathogenesis of neurological diseases.Frontiers in molecular neuroscience · 2022Review
Corrections and comments
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Authors and funding
18 authors at 7 institutions in 2 countries.
Funding
Abstract
The translocase of outer mitochondrial membrane (TOMM) complex is the entry gate for virtually all mitochondrial proteins and is essential to build the mitochondrial proteome. TOMM70 is a receptor that assists mainly in mitochondrial protein import. Here, we report two individuals with de novo variants in the C-terminal region of TOMM70. While both individuals exhibited shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities, there were differences between the two individuals, most prominently the age of symptom onset. Both individuals were undiagnosed despite extensive genetics workups. Individual 1 was found to have a p.Thr607Ile variant while Individual 2 was found to have a p.Ile554Phe variant in TOMM70. To functionally assess both TOMM70 variants, we replaced the Drosophila Tom70 coding region with a Kozak-mini-GAL4 transgene using CRISPR-Cas9. Homozygous mutant animals die as pupae, but lethality is rescued by the mini-GAL4-driven expression of human UAS-TOMM70 cDNA. Both modeled variants lead to significantly less rescue indicating that they are loss-of-function alleles. Similarly, RNAi-mediated knockdown of Tom70 in the developing eye causes roughening and synaptic transmission defect, common findings in neurodegenerative and mitochondrial disorders. These phenotypes were rescued by the reference, but not the variants, of TOMM70. Altogether, our data indicate that de novo loss-of-function variants in TOMM70 result in variable white matter disease and neurological phenotypes in affected individuals.
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Registered trials
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