Matsumoto Naoto, Kaneko Minami, Watanabe Natsumi, Itaoka Misa, Seki Yoich, Morimoto Takako, Torii Tomohiro, Miyamoto Yuki, Yamauchi Junji
Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Biochem Biophys Res Commun. 2018 Apr 30;499(1):78-85. doi: 10.1016/j.bbrc.2018.03.136. Epub 2018 Mar 21.
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 the polr1c gene, 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.
特雷彻·柯林斯综合征（TCS）是一种颅面发育障碍，其关键特征是多种症状的组合。例如，患者可能出现双侧睑裂向下倾斜、下眼睑缺损、面部骨骼发育不全、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）。在第279位精氨酸处已发现两种已知的错义突变（精氨酸279突变为谷氨酰胺[R279Q]和精氨酸279突变为色氨酸[R279W]）。然而，这两种突变或每个单独的突变是否以及如何影响POLR1C的细胞特性仍有待阐明。在此我们表明，与TCS3相关的错义突变导致POLR1C在细胞内定位异常，从而抑制软骨形成分化。野生型POLR1C通常定位于细胞核中。主要发现R279Q或R279W突变体定位于溶酶体中。在小鼠软骨形成ATDC5细胞中表达R279Q或R279W突变体可降低4E-BP1和核糖体S6蛋白的磷酸化，这两种蛋白属于在溶酶体中起关键作用的哺乳动物雷帕霉素靶蛋白（mTOR）信号通路。此外，R279Q或R279W突变体的表达抑制了ATDC5细胞中的软骨形成分化。综上所述，与TCS3相关的突变导致POLR1C定位于溶酶体并抑制软骨形成分化，这可能解释了特雷彻·柯林斯综合征潜在病理分子基础的一部分。
