This report describes a newly defined neurological disorder associated with de novo variants of the TOMM70 gene. TOMM70 encodes a component of the translocase of outer mitochondrial membrane (TOMM) complex; the TOMM70 receptor accelerates the import of all mitochondrial precursor proteins. There is a single orthologous gene in Drosophila, Tom70, for which loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human Hsap\TOMM70 gene have been introduced into flies, including wild-type and the variants implicated in disease. Variant(s) implicated in human disease tested (as transgenic human gene, TOMM70): T607I and I554F variant forms of the human gene have been introduced into flies.
Animals homozygous for Dmel\Tom70 loss-of-function mutations typically die during the pupal stage.
Ubiquitous expression of the human Hsap\TOMM70 gene, whether wild-type or variant, fails to produce any obvious phenotypes. Heterologous rescue (functional complementation) is observed for the pupal lethal phenotype of Dmel\Tom70 loss-of-function mutations. Expression the wild-type human gene results in almost complete rescue of the Tom70 pupal lethal phenotype. The two disease-implicated variants effect only partial rescue, supporting the hypothesis that they are partial loss-of-function mutations. Based on this assay, T607I retains more function than I554F.
[updated Aug. 2020 by FlyBase; FBrf0222196]
Two individuals have been described. They 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 (FBrf0245837).
The isolated mutations occurred de novo and were heterozygous (FBrf0245837).
The TOMM70 gene is described as intolerant to loss-of-function variation in the human population (FBrf0245837 and references cited therein).
TOMM70 is a nuclear gene that encodes an import receptor of the outer mitochondrial membrane that is part of the translocase of the outer membrane complex (TOMM). The TOMM70 receptor accelerates the import of all mitochondrial precursor proteins. [Gene Cards, TOMM70; 2020.08.17]
The coordinated action of the translocase of inner mitochondrial membrane (TIMM) and translocase of outer mitochondrial membrane (TOMM) complexes is required for the import of nuclear-encoded mitochondrial proteins into the mitochondria. In human, TOMM70 gene is broadly expressed in many organs including the central nervous system (FBrf0245837 and references cited therein).
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human TOMM70 (1 Drosophila to 1 human). Dmel\Tom70 shares 40% identity and 60% similarity with the human gene.
