Purpose

Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2–1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly.

Methods

We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish.

Results

We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives.

Conclusion

Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.

中文翻译：

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Treacher Collins 综合征 4 型中的 POLR1B 和神经嵴细胞异常。

目的

Treacher Collins 综合征 (TCS) 是一种罕见的常染色体显性遗传的下颌面骨发育不全，患病率为 0.2-1/10,000。特征包括由于异常的神经嵴细胞 (NCC) 迁移和分化导致的双侧和对称颧骨和下颌发育不全和面部异常。迄今为止，已鉴定出三个基因：TCOF1、POLR1C和POLR1D。尽管有大量患者进行了分子诊断，但仍有一些患者没有已知的遗传异常。

方法

我们对四名 TCS 患者进行了外显子组测序，但他们对已知致病基因的致病变异呈阴性。在斑马鱼中研究了致病变异的影响。

结果

我们在POLR1B中发现了三个新的致病变异。斑马鱼中polr1b的敲低诱导了一种类似于 TCS 的异常颅面表型，这与改变的核糖体基因表达、神经上皮中大量 p53 相关的细胞凋亡和 NCC 衍生物的数量减少有关。

结论

RNA 聚合酶 I 亚基 POLR1B 的致病性变异可能在受限的神经上皮区域诱导大量 p53 依赖性细胞凋亡，改变 NCC 迁移并导致颅骨畸形。我们将POLR1B鉴定为导致新型 TCS 综合征 (TCS4) 的新致病基因，并在斑马鱼中建立了一个新的实验模型来研究 POLR1B 相关的 TCS。