Berenguer Marie, Tingaud-Sequeira Angele, Colovati Mileny, Melaragno Maria I, Bragagnolo Silvia, Perez Ana B A, Arveiler Benoit, Lacombe Didier, Rooryck Caroline
Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, University Bordeaux, Bordeaux, France.
Division of Genetics, Department of Morphology and Genetics, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
Eur J Hum Genet. 2017 Sep;25(9):1083-1086. doi: 10.1038/ejhg.2017.101. Epub 2017 Jun 14.
Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by hemifacial microsomia associated with ear, eyes and vertebrae malformations showing highly variable expressivity. Recently, MYT1, encoding the myelin transcription factor 1, was reported as the first gene involved in OAVS, within the retinoic acid (RA) pathway. Fifty-seven OAVS patients originating from Brazil were screened for MYT1 variants. A novel de novo missense variant affecting function, c.323C>T (p.(Ser108Leu)), was identified in MYT1, in a patient presenting with a severe form of OAVS. Functional studies showed that MYT1 overexpression downregulated all RA receptors genes (RARA, RARB, RARG), involved in RA-mediated transcription, whereas no effect was observed on CYP26A1 expression, the major enzyme involved in RA degradation, Moreover, MYT1 variants impacted significantly the expression of these genes, further supporting their pathogenicity. In conclusion, a third variant affecting function in MYT1 was identified as a cause of OAVS. Furthermore, we confirmed MYT1 connection to RA signaling pathway.
眼-耳-脊椎综合征（OAVS）是一种发育障碍，其特征为半侧颜面短小畸形，并伴有耳、眼和脊椎畸形，表现出高度可变的表达性。最近，编码髓磷脂转录因子1的MYT1被报道为视黄酸（RA）途径中首个与OAVS相关的基因。对来自巴西的57例OAVS患者进行了MYT1变异筛查。在一名患有严重形式OAVS的患者中，在MYT1中鉴定出一种影响功能的新型新生错义变异，即c.323C>T（p.(Ser108Leu)）。功能研究表明，MYT1过表达下调了所有参与RA介导转录的RA受体基因（RARA、RARB、RARG），而对参与RA降解的主要酶CYP26A1的表达没有影响。此外，MYT1变异显著影响这些基因的表达，进一步支持了它们的致病性。总之，在MYT1中鉴定出的第三种影响功能的变异被确定为OAVS的一个病因。此外，我们证实了MYT1与RA信号通路的关联。
