Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay

doi:10.1038/s10038-019-0714-1

Case Reports

. 2020 Mar;65(3):231-240.

doi: 10.1038/s10038-019-0714-1. Epub 2020 Jan 6.

Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay

Xiujuan Wei^#¹, Miaomiao Du^#¹, Jie Xie^#¹, Ting Luo¹, Yan Zhou¹, Kun Zhang¹, Jin Li¹, Deyu Chen¹, Pu Xu¹, Manli Jia¹, Huaibin Zhou¹, Hezhi Fang², Jianxin Lyu^{3

4}, Yanling Yang⁵

Affiliations

¹ Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
² Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. hezhifang990909@gmail.com.
³ Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. jxlu313@163.com.
⁴ Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, 310053, Zhejiang, China. jxlu313@163.com.
⁵ Department of Pediatrics, Peking University First Hospital, 100034, Beijing, China. organic.acid@126.com.

^# Contributed equally.

PMID: 31907385
DOI: 10.1038/s10038-019-0714-1

Case Reports

Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay

Xiujuan Wei et al. J Hum Genet. 2020 Mar.

. 2020 Mar;65(3):231-240.

doi: 10.1038/s10038-019-0714-1. Epub 2020 Jan 6.

Authors

Xiujuan Wei^#¹, Miaomiao Du^#¹, Jie Xie^#¹, Ting Luo¹, Yan Zhou¹, Kun Zhang¹, Jin Li¹, Deyu Chen¹, Pu Xu¹, Manli Jia¹, Huaibin Zhou¹, Hezhi Fang², Jianxin Lyu^{3

4}, Yanling Yang⁵

Affiliations

¹ Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
² Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. hezhifang990909@gmail.com.
³ Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. jxlu313@163.com.
⁴ Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, 310053, Zhejiang, China. jxlu313@163.com.
⁵ Department of Pediatrics, Peking University First Hospital, 100034, Beijing, China. organic.acid@126.com.

^# Contributed equally.

PMID: 31907385
DOI: 10.1038/s10038-019-0714-1

Abstract

TOM70 is a member of the TOM complex that transports cytosolic proteins into mitochondria. Here, we identified two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] from a patient with severe anemia, lactic acidosis, and developmental delay. Patient-derived immortalized lymphocytes showed decreased TOM70 expression, oligomerized TOM70 complex, and TOM 20/22/40 complex compared with expression in control lymphocytes. Functional analysis revealed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects, with complex IV being primarily affected. As a result, patient-derived cells grew slower in galactose medium and generated less ATP and more extracellular lactic acid than did control cells. In vitro cell model compensatory experiments confirmed the pathogenicity of TOMM70 variants since only wild-type TOM70, but not mutant TOM70, could restore the complex IV defect and TOM70 expression in TOM70 knockdown U2OS cells. Altogether, we report the first case of mitochondrial disease-causing mutations in TOMM70 and demonstrate that TOM70 is essential for multi-OXPHOS assembly. Mutational screening of TOMM70 should be employed to identify mitochondrial disease-causing gene mutations in the future.

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References

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1. Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, et al. Mitochondrial diseases. Nat Rev Dis Prim. 2016;2:16080. - DOI
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[1] Craven L, Alston CL, Taylor RW, Turnbull DM. Recent advances in mitochondrial disease. Annu Rev Genom Hum Genet. 2017;18:257–75. - DOI

[2] Craven L, Alston CL, Taylor RW, Turnbull DM. Recent advances in mitochondrial disease. Annu Rev Genom Hum Genet. 2017;18:257–75. - DOI

[3] Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, et al. Mitochondrial diseases. Nat Rev Dis Prim. 2016;2:16080. - DOI

[4] Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, et al. Mitochondrial diseases. Nat Rev Dis Prim. 2016;2:16080. - DOI

[5] Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, et al. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell. 2013;155:160–71. - DOI

[6] Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, et al. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell. 2013;155:160–71. - DOI

[7] Strauss KA, Jinks RN, Puffenberger EG, Venkatesh S, Singh K, Cheng I, et al. CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. Am J Hum Genet. 2015;96:121–35. - DOI

[8] Strauss KA, Jinks RN, Puffenberger EG, Venkatesh S, Singh K, Cheng I, et al. CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. Am J Hum Genet. 2015;96:121–35. - DOI

[9] Wortmann SB, Vaz FM, Gardeitchik T, Vissers LE, Renkema GH, Schuurs-Hoeijmakers JH, et al. Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat Genet. 2012;44:797–802. - DOI

[10] Wortmann SB, Vaz FM, Gardeitchik T, Vissers LE, Renkema GH, Schuurs-Hoeijmakers JH, et al. Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat Genet. 2012;44:797–802. - DOI

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Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay

Affiliations

Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay

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