Fazeli Walid, Herkenrath Peter, Stiller Barbara, Neugebauer Antje, Fricke Julia, Lang-Roth Ruth, Nürnberg Gudrun, Thoenes Michaela, Becker Jutta, Altmüller Janine, Volk Alexander E, Kubisch Christian, Heller Raoul
Department of Pediatrics, University Hospital Cologne, 50937 Cologne, Germany.
Institute for Molecular and Behavioral Neuroscience, University of Cologne, 50937 Cologne, Germany.
Hum Mol Genet. 2017 Oct 15;26(20):4055-4066. doi: 10.1093/hmg/ddx296.
Congenital cranial dysinnervation disorders (CCDDs) comprise a heterogeneous spectrum of diseases characterized by congenital, non-progressive impairment of eye, eyelid and/or facial movements including Möbius syndrome, Duane retraction syndrome, congenital ptosis, and congenital fibrosis of the extraocular muscles. Over the last 20 years, several CCDDs have been identified as neurodevelopmental disorders that are caused by mutations of genes involved in brain and cranial nerve development, e.g. KIF21A and TUBB3 that each plays a pivotal role for microtubule function. In a five-generation pedigree, we identified a heterozygous mutation of TUBB6, a gene encoding a class V tubulin which has not been linked to a human hereditary disease so far. The missense mutation (p.Phe394Ser) affects an amino acid residue highly conserved in evolution, and co-segregates with a phenotype characterized by congenital non-progressive bilateral facial palsy and congenital velopharyngeal dysfunction presenting with varying degrees of hypomimia, rhinophonia, impaired gag reflex and bilateral ptosis. Expression of the mutated protein in yeast led to an impaired viability compared to wildtype cells when exposed to the microtubule-poison benomyl. Our findings enlarge the spectrum of tubulinopathies and emphasize that mutations of TUBB6 should be considered in patients with congenital non-progressive facial palsy. Further studies are needed to verify whether this phenotype is indeed part of the CCDD spectrum.
先天性颅神经支配障碍（CCDDs）包括一系列异质性疾病，其特征为先天性、非进行性的眼部、眼睑和/或面部运动障碍，包括莫比乌斯综合征、杜安眼球后退综合征、先天性上睑下垂和眼外肌先天性纤维化。在过去20年中，几种CCDDs已被确定为神经发育障碍，由参与脑和颅神经发育的基因突变引起，例如KIF21A和TUBB3，它们在微管功能中各自发挥关键作用。在一个五代家系中，我们鉴定出TUBB6基因的杂合突变，该基因编码V类微管蛋白，迄今为止尚未与人类遗传性疾病相关联。错义突变（p.Phe394Ser）影响一个在进化中高度保守的氨基酸残基，并与一种表型共分离，该表型的特征为先天性非进行性双侧面瘫和先天性腭咽功能障碍，伴有不同程度的表情减少、鼻音、咽反射受损和双侧上睑下垂。与野生型细胞相比，当暴露于微管毒物苯菌灵时，酵母中突变蛋白的表达导致活力受损。我们的发现扩大了微管蛋白病的范围，并强调对于先天性非进行性面瘫患者应考虑TUBB6突变。需要进一步研究以验证该表型是否确实是CCDD谱系的一部分。
