Carré Aurore, Stoupa Athanasia, Kariyawasam Dulanjalee, Gueriouz Manelle, Ramond Cyrille, Monus Taylor, Léger Juliane, Gaujoux Sébastien, Sebag Frédéric, Glaser Nicolas, Zenaty Delphine, Nitschke Patrick, Bole-Feysot Christine, Hubert Laurence, Lyonnet Stanislas, Scharfmann Raphaël, Munnich Arnold, Besmond Claude, Taylor William, Polak Michel
INSERM U1016, Cochin Institute, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
IMAGINE Institute affiliate, Paris, France.
Hum Mol Genet. 2017 Feb 1;26(3):599-610. doi: 10.1093/hmg/ddw419.
Congenital hypothyroidism is the most common neonatal endocrine disorder and is primarily caused by developmental abnormalities otherwise known as thyroid dysgenesis (TD). We performed whole exome sequencing (WES) in a consanguineous family with TD and subsequently sequenced a cohort of 134 probands with TD to identify genetic factors predisposing to the disease. We identified the novel missense mutations p.S148F, p.R114Q and p.L177W in the BOREALIN gene in TD-affected families. Borealin is a major component of the Chromosomal Passenger Complex (CPC) with well-known functions in mitosis. Further analysis of the missense mutations showed no apparent effects on mitosis. In contrast, expression of the mutants in human thyrocytes resulted in defects in adhesion and migration with corresponding changes in gene expression suggesting others functions for this mitotic protein. These results were well correlated with the same gene expression pattern analysed in the thyroid tissue of the patient with BOREALIN-p.R114W. These studies open new avenues in the genetics of TD in humans.
先天性甲状腺功能减退症是最常见的新生儿内分泌疾病，主要由发育异常引起，即所谓的甲状腺发育不全（TD）。我们对一个患有TD的近亲家庭进行了全外显子组测序（WES），随后对134名TD先证者进行了测序，以确定导致该疾病的遗传因素。我们在受TD影响的家庭中鉴定出BOREALIN基因中的新错义突变p.S148F、p.R114Q和p.L177W。Borealin是染色体乘客复合体（CPC）的主要成分，在有丝分裂中具有众所周知的功能。对这些错义突变的进一步分析表明，它们对有丝分裂没有明显影响。相反，突变体在人甲状腺细胞中的表达导致黏附和迁移缺陷，基因表达也相应改变，这表明这种有丝分裂蛋白具有其他功能。这些结果与对携带BOREALIN-p.R114W的患者甲状腺组织分析的相同基因表达模式密切相关。这些研究为人类TD的遗传学研究开辟了新途径。
