Alternative titles; symbols
HGNC Approved Gene Symbol: TOMM70
Cytogenetic location: 3q12.2 Genomic coordinates (GRCh38) : 3:100,363,431-100,401,089 (from NCBI)
The translocase of outer mitochondrial membrane (TOM) complex is a multisubunit complex involved in the recognition, unfolding, and translocation of preproteins into the mitochondria. See TIM17A (605057).
By screening a brain cDNA library for cDNAs encoding proteins larger than 50 kD, Nagase et al. (1998) isolated a cDNA encoding TOMM70A, which they called KIAA0719. The 608-amino acid protein is 29% identical to the mitochondrial precursor protein import receptor of Neurospora crassa. RT-PCR analysis detected ubiquitous expression of KIAA0719, with relatively weak expression in pancreas, testis, and spleen.
Thyroid hormone is an important regulator of mammalian brain maturation and acts by regulating gene expression by binding to its high-affinity receptor (see 190160), a ligand-regulated transcription factor. To isolate genes regulated by thyroid hormone in the central nervous system, Alvarez-Dolado et al. (1999) used differential display RT-PCR with RNA from dissected control and hypothyroid rat cortex, cerebellum, striatum, and hippocampus. They isolated a rat cDNA almost identical to the human TOMM70A cDNA (KIAA0719) isolated by Nagase et al. (1998), which shares homology with fungal Tom70. Northern blot analysis revealed expression of 4.2- and 2.0-kb Tomm70a transcripts in control rat and T4-treated hypothyroid rat striatum in the early postnatal period. In situ hybridization analysis showed expression throughout the brains of control rats. Alvarez-Dolado et al. (1999) concluded that Tomm70a expression in specific brain areas is under thyroid control during the early postnatal period.
Young et al. (2003) showed that the cytosolic chaperones HSP90 (140571) and HSP70 (140550) dock onto a specialized tetratricopeptide (TPR) domain in the import receptor TOMM70 at the outer mitochondrial membrane. This interaction served to deliver a set of preproteins to the receptor for subsequent membrane translocation dependent on the HSP90 ATPase. Disruption of the chaperone/TOMM70 recognition inhibited the import of these preproteins into mitochondria. Young et al. (2003) proposed a mechanism in which chaperones are recruited for a specific targeting event by a membrane-bound receptor.
Nagase et al. (1998) mapped the TOMM70A gene to chromosome 3 by radiation hybrid analysis.
Associations Pending Confirmation
For discussion of a possible association between compound heterozygous variants in the TOMM70 gene and combined oxidative phosphorylation deficiency (COXPD; see 609060), see 606081.0001.
Dutta et al. (2020) reported 2 unrelated patients with variable neurologic features who were found by next-generation sequencing to carry de novo heterozygous missense variants in the C-terminal region of the TOMM70 gene. Patient 1 was a 7-year-old girl with a T607I variant (c.1820C-T, NM_014820.3). She had severe global developmental delay, mild acquired microcephaly, hypotonia, and a mixed hyperkinetic movement disorder with choreoathetosis, dystonia, and ataxia. Brain imaging showed hypomyelination, thin corpus callosum, and cerebellar atrophy. Patient 2 was a 12-year-old boy with an I554F variant (c.1660A-T, NM_014820.3). He presented with episodic regression at 4 years of age following normal early development. He had gross motor impairment with altered gait, hypotonia and proximal muscle weakness, spastic ataxia, cogwheeling, and truncal titubation. Other features included dysmetria, dysarthria, ptosis, and increasing academic difficulties. Brain imaging showed diffuse T2-weighted hyperintensities in the deep white matter and other areas of the brain, including the cerebellum. Metabolic testing was unremarkable in both patients, and neither carried defects in the mitochondrial genome. Neither variant was present in the gnomAD database. Expression of wildtype TOMM70, but not the variants, rescued lethality and other neurodegenerative defects associated with loss of Tomm70 in Drosophila. These findings suggested that the variants identified in the patients are partial loss-of-function alleles that result in neurologic impairment.
This variant is classified as a variant of unknown significance because its contribution to combined oxidative phosphorylation deficiency (COXPD; see 609060) has not been confirmed.
In an 11-year-old boy, born of unrelated Han Chinese parents, with a metabolic disorder associated with combined oxidative phosphorylation deficiency, Wei et al. (2020) identified compound heterozygous missense variants in the TOMM70 gene: a c.794C-T transition in exon 4, resulting in a thr265-to-met (T265M) substitution, and a c.1745C-T transition in exon 11, resulting in an ala582-to-val (A582V; 606081.0002) substitution. The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family: each unaffected parent was heterozygous for one of the variants. Both variants occurred at highly conserved residues and were found at very low frequencies (0.00007415 and 0.00001648, respectively) in heterozygous state in the gnomAD database. Western blot analysis of patient-derived lymphocytes showed decreased TOMM70 protein expression compared to controls, suggesting instability of the mutant proteins. There was evidence of decreased assembly of higher macromolecules of the TOMM complex. The patient presented with hypoglycemia and mild anemia soon after birth. Bone marrow biopsy indicated hypochromic microcytic anemia. Serum lactate was increased, although it normalized over time. Later in childhood, he had normal language development and neurologic examination, but showed mild muscle weakness, poor overall growth with small head circumference, and delayed bone age. Detailed studies of patient-derived lymphocytes showed decreased steady-state levels of mitochondrial respiratory enzyme complexes I, III, IV, and V, with complex IV being most affected. However, functional studies showed impaired activity of complex IV, whereas the activity of the other complexes was similar to controls. Patient cells grew slower in galactose medium and generated less ATP than controls, suggesting a mitochondrial defect. In vitro studies showed that these TOMM70 variants were unable to rescue a complex IV defect and TOMM70 expression in U2OS cells in which TOMM70 expression was silenced with siRNA. The findings suggested that the variants are pathogenic and impair TOMM70 function.
This variant is classified as a variant of unknown significance because its contribution to combined oxidative phosphorylation deficiency (COXPD; see 609060) has not been confirmed.
For discussion of the c.1745C-T transition (c.1745C-T, NM_014820.5) in exon 11 of the TOMM70 gene, resulting in an ala582-to-val (A582V) substitution, that was found in compound heterozygous state in a patient with a COXPD phenotype by Wei et al. (2020), see 606081.0001.
Alvarez-Dolado, M., Gonzalez-Moreno, M., Valencia, A., Zenke, M., Bernal, J., Munoz, A. Identification of a mammalian homologue of the fungal Tom70 mitochondrial precursor protein import receptor as a thyroid hormone-regulated gene in specific brain regions. J. Neurochem. 73: 2240-2249, 1999. [PubMed: 10582581] [Full Text: https://doi.org/10.1046/j.1471-4159.1999.0732240.x]
Dutta, D., Briere, L. C., Kanca, O., Marcogliese, P. C., Walker, M. A., High, F. A., Vanderver, A., Krier, J., Carmichael, N., Callahan, C., Taft, R. J., Simons, C., Helman, G., Undiagnosed Diseases Network, Wangler, M. F., Yamamoto, S., Sweetser, D. A., Bellen, H. J. De novo mutations in TOMM70, a receptor of the mitochondrial import translocase, cause neurological impairment. Hum. Molec. Genet. 29: 1568-1579, 2020. [PubMed: 32356556] [Full Text: https://doi.org/10.1093/hmg/ddaa081]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452] [Full Text: https://doi.org/10.1093/dnares/5.5.277]
Wei, X., Du, M., Xie, J., Luo, T., Zhou, Y., Zhang, K., Li, J., Chen, D., Xu, P., Jia, M., Zhou, H., Fang, H., Lyu, J., Yang, Y. Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay. J. Hum. Genet. 65: 231-240, 2020. [PubMed: 31907385] [Full Text: https://doi.org/10.1038/s10038-019-0714-1]
Young, J. C., Hoogenraad, N. J., Hartl, F. U. Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70. Cell 112: 41-50, 2003. [PubMed: 12526792] [Full Text: https://doi.org/10.1016/s0092-8674(02)01250-3]