MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration
MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration
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DOI：
10.1093/hmg/ddz066
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发表时间：
2019-07-15
影响因子：
3.5
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
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作者：
Hamanaka, Kohei;Takata, Atsushi;Matsumoto, Naomichi
性发育障碍（DSD）被定义为染色体、性腺或解剖性别不典型的先天性疾病。在许多DSD病例中，遗传原因仍有待阐明。在这里，我们进行了一项病例对照外显子组测序研究，比较了26例DSD病例和2625例对照之间罕见破坏性变异的基因负担。我们发现，在编码髓鞘调节因子（一种对少突胶质细胞发育至关重要的转录因子）的MYRF基因中，外显子组范围内罕见的杂合截短变体显著富集。所有这三种变体都是重新发生的。我们在一个独立的队列中发现了另外一例46，XY DSD新发损伤性错义变异病例。46，XX例DSD患者的临床症状包括苗勒氏衍生物和卵巢发育不全，46，XY例DSD患者的支持细胞和间质细胞发育缺陷，1例46，XY例DSD患者的先天性腹股沟疝。由于所有这些细胞和组织都是或部分由体腔上皮（CE）衍生的细胞（CEDC）组成，CEDC通过增殖和迁移由CE发育而来，MYRF可能与这些过程有关。与这一假设相一致，胎儿性腺的单细胞RNA测序揭示了MYRF在CE和CEDC中的高表达。对大鼠Myrf的公开染色质免疫沉淀测序数据的再分析表明，在Myrf的推定靶基因中，调节增殖和迁移的基因富集。提示MYRF是46，XY和46，XX DSD的新致病基因，MYRF是调节CD和/或CEDC增殖和迁移的转录因子，对多器官的发育至关重要。
Disorders of sex development (DSDs) are defined as congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. In many DSD cases, genetic causes remain to be elucidated. Here, we performed a case-control exome sequencing study comparing gene-based burdens of rare damaging variants between 26 DSD cases and 2625 controls. We found exome-wide significant enrichment of rare heterozygous truncating variants in the MYRF gene encoding myelin regulatory factor, a transcription factor essential for oligodendrocyte development. All three variants occurred de novo. We identified an additional 46,XY DSD case of a de novo damaging missense variant in an independent cohort. The clinical symptoms included hypoplasia of Mullerian derivatives and ovaries in 46,XX DSD patients, defective development of Sertoli and Leydig cells in 46,XY DSD patients and congenital diaphragmatic hernia in one 46,XY DSD patient. As all of these cells and tissues are or partly consist of coelomic epithelium (CE)-derived cells (CEDC) and CEDC developed from CE via proliferaiton and migration, MYRF might be related to these processes. Consistent with this hypothesis, single-cell RNA sequencing of foetal gonads revealed high expression of MYRF in CE and CEDC. Reanalysis of public chromatin immunoprecipitation sequencing data for rat Myrf showed that genes regulating proliferation and migration were enriched among putative target genes of Myrf. These results suggested that MYRF is a novel causative gene of 46,XY and 46,XX DSD and MYRF is a transcription factor regulating CD and/or CEDC proliferation and migration, which is essential for development of multiple organs.