A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay
Cameron Young,
Dominyka Batkovskyte,
Miyuki Kitamura,
Maria Shvedova,
Yutaro Mihara,
Jun Akiba,
Wen Zhou,
Anna Hammarsjö,
Gen Nishimura,
Shuichi Yatsuga,
Giedre Grigelioniene,
Tatsuya Kobayashi
Affiliations
Cameron Young
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Dominyka Batkovskyte
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17177, Sweden
Miyuki Kitamura
Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
Maria Shvedova
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Yutaro Mihara
Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
Jun Akiba
Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan
Wen Zhou
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Anna Hammarsjö
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17177, Sweden; Department of Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm 17176, Sweden
Gen Nishimura
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17177, Sweden; Center for Intractable Disease, Saitama Medical University Hospital, Saitama, Japan
Shuichi Yatsuga
Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; Department of Pediatrics, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan
Giedre Grigelioniene
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17177, Sweden; Department of Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm 17176, Sweden; Department of Clinical Genetics, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping 58183, Sweden; Corresponding author
Tatsuya Kobayashi
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Corresponding author
Summary: Mitochondrial diseases are a heterogeneous group of genetic disorders caused by pathogenic variants in genes encoding gene products that regulate mitochondrial function. These genes are located either in the mitochondrial or in the nuclear genome. The TOMM7 gene encodes a regulatory subunit of the translocase of outer mitochondrial membrane (TOM) complex that plays an essential role in translocation of nuclear-encoded mitochondrial proteins into mitochondria. We report an individual with a homozygous variant in TOMM7 (c.73T>C, p.Trp25Arg) that presented with a syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. Analysis of mouse models strongly suggested that the identified variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with homozygous Tomm7 deletion. These Tomm7 mutant mice show pathological changes consistent with mitochondrial dysfunction, including growth defects, severe lipoatrophy, and lipid accumulation in the liver. These mice die prematurely following a rapidly progressive weight loss during the last week of their lives. Tomm7 deficiency causes a unique alteration in mitochondrial function; despite the bioenergetic deficiency, mutant cells show increased oxygen consumption with normal responses to electron transport chain (ETC) inhibitors, suggesting that Tomm7 deficiency leads to an uncoupling between oxidation and ATP synthesis without impairing the function of the tricarboxylic cycle metabolism or ETC. This study presents evidence that a hypomorphic variant in one of the genes encoding a subunit of the TOM complex causes mitochondrial disease.
