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A hypomorphic varia...
A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay
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- Young, Cameron (author)
- Massachusetts Gen Hosp, MA 02114 USA; Harvard Med Sch, MA 02114 USA
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- Batkovskyte, Dominyka (author)
- Karolinska Institutet,Karolinska Inst, Sweden
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- Kitamura, Miyuki (author)
- Kurume Univ, Japan
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- Shvedova, Maria (author)
- Massachusetts Gen Hosp, MA 02114 USA; Harvard Med Sch, MA 02114 USA
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- Mihara, Yutaro (author)
- Kurume Univ, Japan
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- Akiba, Jun (author)
- Kurume Univ Hosp, Japan
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- Zhou, Wen (author)
- Massachusetts Gen Hosp, MA 02114 USA; Harvard Med Sch, MA 02114 USA
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- Hammarsjo, Anna (author)
- Karolinska Institutet,Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden
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- Nishimura, Gen (author)
- Karolinska Inst, Sweden; Saitama Med Univ Hosp, Japan
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- Yatsuga, Shuichi (author)
- Kurume Univ, Japan; Fukuoka Univ, Japan
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- Grigelioniene, Giedre (author)
- Karolinska Institutet,Linköpings universitet,Institutionen för biomedicinska och kliniska vetenskaper,Medicinska fakulteten,Region Östergötland, Klinisk genetik,Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden
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- Kobayashi, Tatsuya (author)
- Massachusetts Gen Hosp, MA 02114 USA; Harvard Med Sch, MA 02114 USA
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(creator_code:org_t)
- ELSEVIER, 2023
- 2023
- English.
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In: Human Genetics and Genomics Advances. - : ELSEVIER. - 2666-2477. ; 4:1
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Genetik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Genetics (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Young, Cameron
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Batkovskyte, Dom ...
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Kitamura, Miyuki
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Shvedova, Maria
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Mihara, Yutaro
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Akiba, Jun
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show more...
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Zhou, Wen
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Hammarsjo, Anna
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Nishimura, Gen
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Yatsuga, Shuichi
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Grigelioniene, G ...
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Kobayashi, Tatsu ...
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Genetics
- Articles in the publication
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Human Genetics a ...
- By the university
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Linköping University
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Karolinska Institutet