Treacher Collins syndrome 3 (TCS3)-associated POLR1C mutants are localized in the lysosome and inhibits chondrogenic differentiation.
Treacher Collins syndrome 3 (TCS3)-associated POLR1C mutants are localized in the lysosome and inhibits chondrogenic differentiation.
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DOI：
10.1016/j.bbrc.2018.03.136
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发表时间：
2018-04
影响因子：
3.1
通讯作者：
N. Matsumoto;Minami Kaneko;Natsumi Watanabe;Misa Itaoka;Y. Seki;T. Morimoto;Tomohiro Torii;Y. Miyamoto;Keiichi Homma;J. Yamauchi
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文献类型：
--
作者：
N. Matsumoto;Minami Kaneko;Natsumi Watanabe;Misa Itaoka;Y. Seki;T. Morimoto;Tomohiro Torii;Y. Miyamoto;Keiichi Homma;J. Yamauchi
Treacher Collins 综合征 (TCS) 是一种颅面发育障碍，其主要特征是症状的组合。例如，患者可能患有双侧睑裂向下倾斜、下眼睑缺损、面骨发育不全、腭裂、外耳畸形和外耳道闭锁。 TCS3 是由 polr1c 基因突变引起的，该基因编码 RNA 聚合酶 I 和 III 亚基 C (POLR1C)。 Arg-279 位点存在两个已知的错义突变（Arg279-to-Gln [R279Q] 和 Arg279-to-Trp [R279W]）。然而，两个或每个突变是否或如何影响 POLR1C 的细胞特性仍有待澄清。在这里，我们发现 TCS3 相关的错义突变导致 POLR1C 的异常细胞内定位，抑制软骨形成分化。野生型 POLR1C 通常位于细胞核中。 R279Q 或 R279W 突变体主要位于溶酶体中。小鼠软骨形成 ATDC5 细胞中 R279Q 或 R279W 突变体的表达降低了 4E-BP1 和核糖体 S6 蛋白的磷酸化，这些蛋白属于哺乳动物雷帕霉素靶标 (mTOR) 信号传导，在溶酶体中发挥关键作用。此外，R279Q或R279W突变体的表达抑制ATDC5细胞中的软骨形成分化。总而言之，TCS3 相关突变导致 POLR1C 定位到溶酶体中并抑制软骨分化，这可能解释了 Treacher Collins 综合征的部分病理分子基础。
Treacher Collins syndrome (TCS) is a craniofacial developmental disorder whose key feature is a combination of symptoms. For example, a patient could have bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids, hypoplasia of the facial bones, cleft palate, malformation of the external ears, and atresia of the external auditory canals. TCS3 is caused by mutations of thepolr1cgene, which encodes RNA polymerase I and III subunit C (POLR1C). There have been two known missense mutations (Arg279-to-Gln [R279Q] and Arg279-to-Trp [R279W]) at the Arg-279 position. However, it remains to be clarified whether or how both or each individual mutation affects the cellular properties of POLR1C. Here we show that TCS3-associated missense mutations cause aberrant intracellular localization of POLR1C, inhibiting chondrogenic differentiation. The wild type POLR1C is normally localized in the nuclei. The R279Q or R279W mutant is primarily found to be localized in the lysosome. Expression of the R279Q or R279W mutant in mouse chondrogenic ATDC5 cells decreases phosphorylation of 4E-BP1 and ribosomal S6 proteins, which belong to the mammalian target of rapamycin (mTOR) signaling involved in critical roles in the lysosome. Furthermore, expression of the R279Q or R279W mutant inhibits chondrogenic differentiation in ATDC5 cells. Taken together, TCS3-associated mutation leads to the localization of POLR1C into the lysosome and inhibits chondrogenic differentiation, possibly explaining a portion of the pathological molecular basis underlying Treacher Collins syndrome.