A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
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DOI：
10.1016/j.xhgg.2022.100148
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发表时间：
2023-01-12
期刊：
影响因子：
--
通讯作者：
Kobayashi, Tatsuya
中科院分区：
文献类型：
--
作者：
Young, Cameron;Batkovskyte, Dominyka;Kitamura, Miyuki;Shvedova, Maria;Mihara, Yutaro;Akiba, Jun;Zhou, Wen;Hammarsjo, Anna;Nishimura, Gen;Yatsuga, Shuichi;Grigelioniene, Giedre;Kobayashi, Tatsuya
线粒体疾病是一组异质性的遗传疾病，由编码调节线粒体功能的基因产物的致病变异引起。这些基因位于线粒体或核基因组中。TOMM7基因编码线粒体膜外膜转位酶(TOM)复合体的一个调节亚基，在核编码的线粒体蛋白向线粒体的转位中起重要作用。我们报告一例TOMM7(c.73T>；C，p.Trp25Arg)纯合子变异患者，表现为综合征性身材矮小、骨骼异常、肌肉低张、微泡状肝脂肪变性和发育迟缓。对小鼠模型的分析强烈表明，已识别的变异是亚型的，因为该变异纯合子的小鼠表现出比TOMM7纯合子缺失的小鼠更温和的表型。这些TOMM7突变小鼠表现出与线粒体功能障碍一致的病理变化，包括生长缺陷、严重的脂肪萎缩和肝脏中的脂肪堆积。这些小鼠在生命的最后一周内体重迅速下降后过早死亡。TOMM7缺乏导致线粒体功能的独特改变；尽管存在生物能量缺乏，但突变细胞表现出对电子传递链(ETC)抑制剂正常反应的氧耗增加，这表明TOMM7缺乏导致氧化和ATP合成之间的解偶联，而不损害三羧酸循环代谢等功能。这项研究提供的证据表明，编码TOM复合体的一个亚单位的基因的亚型变异会导致线粒体疾病。Young等人。报道了首例与TOMM7基因错义变异相关的综合征性矮小病例，该基因编码外线粒体膜复合体转位酶的一个调节亚单位。小鼠模型显示，这种变异导致了生物能量缺陷和线粒体疾病的表型。
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. Young et al. reports the first case of syndromic short stature associated with a missense variant in the TOMM7 gene, encoding a regulatory subunit of the translocase of outer mitochondrial membrane complex. Mouse models showed that this variant caused a bioenergetic defect and a phenotype of mitochondrial diseases.
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