Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome.
Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome.
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DOI：
10.1016/j.ajhg.2017.12.017
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发表时间：
2018-02-01
影响因子：
9.8
通讯作者：
Barrio R
中科院分区：
文献类型：
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作者：
Bozal-Basterra L;Martín-Ruíz I;Pirone L;Liang Y;Sigurðsson JO;Gonzalez-Santamarta M;Giordano I;Gabicagogeascoa E;de Luca A;Rodríguez JA;Wilkie AOM;Kohlhase J;Eastwood D;Yale C;Olsen JV;Rauchman M;Anderson KV;Sutherland JD;Barrio R
汤恩斯-布罗克斯综合征（TBS）的特征是手指、耳朵和肾脏的一系列畸形。这些异常与越来越多的纤毛病重叠，这些纤毛病是与初级纤毛形成或功能缺陷有关的遗传综合征。TBS是由编码转录抑制因子SALL1的基因突变引起的，并与位于细胞质上的截断蛋白的存在有关。在这里，我们提供的证据表明，SALL1突变可能通过超出其转录能力的方式导致TBS。通过接近蛋白质组学，我们发现截断的SALL1与纤毛功能相关的因子相互作用，包括纤毛发生的负调控因子CCP110和CEP97。与野生型对照相比，这很可能导致tbs衍生的成纤维细胞、CRISPR/ cas9生成的模型细胞系和tbs模型小鼠胚胎成纤维细胞中更频繁地形成纤毛。此外，tbs样细胞表现出纤毛长度和拆卸率的变化，并与异常的SHH信号转导相结合。这些发现支持了一种假设，即初级纤毛和SHH信号的畸变是TBS表型的促成因素，代表了对TBS病因学理解的范式转变。这些结果为治疗TBS开辟了可能性。
Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS.
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影响因子：
11.8
作者：
Kleylein-Sohn, Julia;Westendorf, Jens;Nigg, Erich A.
通讯作者：
Nigg, Erich A.
影响因子：
30.8
作者：
Kang, S;Graham, JM;Biesecker, LG
通讯作者：
Biesecker, LG
影响因子：
4.8
作者：
Kiefer, SM;McDill, BW;Rauchman, M
通讯作者：
Rauchman, M
DOI：
10.1523/jneurosci.0312-08.2008
发表时间：
2008-07-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Driver EC;Pryor SP;Hill P;Turner J;Rüther U;Biesecker LG;Griffith AJ;Kelley MW
通讯作者：
Kelley MW
影响因子：
21.3
作者：
通讯作者：
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