MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: Bioinformatics consideration

Kohei Hamanaka, Atsushi Takata, Yuri Uchiyama, Satoko Miyatake, Noriko Miyake, Satomi Mitsuhashi, Kazuhiro Iwama, Atsushi Fujita, Eri Imagawa, Ahmed N. Alkanaq, Eriko Koshimizu, Yoshiki Azuma, Mitsuko Nakashima, Takeshi Mizuguchi, Hirotomo Saitsu, Yuka Wada, Sawako Minami, Yuko Katoh-Fukui, Yohei Masunaga, Maki FukamiTomonobu Hasegawa, Tsutomu Ogata, Naomichi Matsumoto

研究成果: Article査読

10 被引用数 (Scopus)


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 Müllerian 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.

ジャーナルHuman molecular genetics
出版ステータスPublished - 2019 7月 15

ASJC Scopus subject areas

  • 分子生物学
  • 遺伝学
  • 遺伝学(臨床)


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