Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy.
Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy.
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DOI：
10.1038/s41467-021-27759-7
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发表时间：
2022-01-10
影响因子：
16.6
通讯作者：
Poché RA
中科院分区：
文献类型：
--
作者：
Chern T;Achilleos A;Tong X;Hill MC;Saltzman AB;Reineke LC;Chaudhury A;Dasgupta SK;Redhead Y;Watkins D;Neilson JR;Thiagarajan P;Green JBA;Malovannaya A;Martin JF;Rosenblatt DS;Poché RA
甲基丙二酸血症和高胱氨酸尿症（cblC）是细胞内钴胺素代谢最常见的先天性缺陷，是由于甲基丙二酸尿症C型和高胱氨酸尿症（MMAHC）的突变所致。最近，转录调节因子HCFC 1和RONIN（THAP 11）的突变被证明会导致cblC的细胞表型。由于HCFC 1/RONIN共同调节MMACHC，因此这些因子突变的患者MMACHC表达减少，并表现出cblC样疾病。然而，额外的失调基因和由此产生的病理生理学是未知的。因此，我们已经产生了这种疾病的小鼠模型。除了表现出之前在cblC中观察到的Mmachc缺失、代谢紊乱和发育缺陷之外，我们还发现了编码核糖体蛋白亚基的靶基因的表达减少。我们还确定了特定的表型，我们归因于在发育过程中影响正常翻译的核糖体生物合成的失调。这些发现将HCFC 1/RONIN鉴定为发育过程中核糖体生物合成的转录调节因子，并且它们的突变导致表现出cblC和核糖体病的复杂综合征。甲基丙二酸血症（MMA）和高同型半胱氨酸血症是维生素B12代谢的先天性缺陷，转录调节因子HCFC 1和RONIN（THAP 11）的突变是这些疾病的某些形式的基础。在这里，作者生成了由RONIN（THAP 11）和HCFC 1突变引起的人类综合征的小鼠模型，并表明这种综合征既是维生素B12代谢的先天性缺陷，也显示了核糖体病的一些特征。
Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies. Combined methylmalonic acidemia (MMA) and hyperhomocysteinemias are inborn errors of vitamin B12 metabolism, and mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) underlie some forms of these disorders. Here the authors generated mouse models of a human syndrome due to mutations in RONIN (THAP11) and HCFC1, and show that this syndrome is both an inborn error of vitamin B12 metabolism and displays some features of ribosomopathy.
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影响因子：
4.2
作者：
Carrillo-Carrasco, Nuria;Chandler, Randy J.;Venditti, Charles P.
通讯作者：
Venditti, Charles P.
影响因子：
4.6
作者：
Fan, GP;Martinowich, K;Sun, YE
通讯作者：
Sun, YE
影响因子：
21.3
作者：
Grewal, SS;Li, L;Edgar, BA
通讯作者：
Edgar, BA
DOI：
10.1038/nrm2467
发表时间：
2008-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Froese, D. Sean;Kopec, Jolanta;Yue, Wyatt W.
通讯作者：
Yue, Wyatt W.