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 Fukami & 3 others Tomonobu Hasegawa, Tsutomu Ogata, Naomichi Matsumoto

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article numberddz066
Pages (from-to)2319-2329
Number of pages11
JournalHuman molecular genetics
Volume28
Issue number14
DOIs
Publication statusPublished - 2019 Jul 15

Fingerprint

XX Disorders of Sex Development 46
Haploinsufficiency
Computational Biology
XY Disorders of Sex Development 46
Disorders of Sex Development
Exome
Epithelium
Genes
Transcription Factors
RNA Sequence Analysis
Leydig Cells
Sertoli Cells
Chromatin Immunoprecipitation
Oligodendroglia
Gonads
Myelin Sheath
Cell Movement
Ovary
Cell Proliferation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Hamanaka, K., Takata, A., Uchiyama, Y., Miyatake, S., Miyake, N., Mitsuhashi, S., ... Matsumoto, N. (2019). MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: Bioinformatics consideration. Human molecular genetics, 28(14), 2319-2329. [ddz066]. https://doi.org/10.1093/hmg/ddz066

MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development : Bioinformatics consideration. / Hamanaka, Kohei; Takata, Atsushi; Uchiyama, Yuri; Miyatake, Satoko; Miyake, Noriko; Mitsuhashi, Satomi; Iwama, Kazuhiro; Fujita, Atsushi; Imagawa, Eri; Alkanaq, Ahmed N.; Koshimizu, Eriko; Azuma, Yoshiki; Nakashima, Mitsuko; Mizuguchi, Takeshi; Saitsu, Hirotomo; Wada, Yuka; Minami, Sawako; Katoh-Fukui, Yuko; Masunaga, Yohei; Fukami, Maki; Hasegawa, Tomonobu; Ogata, Tsutomu; Matsumoto, Naomichi.

In: Human molecular genetics, Vol. 28, No. 14, ddz066, 15.07.2019, p. 2319-2329.

Research output: Contribution to journalArticle

Hamanaka, K, Takata, A, Uchiyama, Y, Miyatake, S, Miyake, N, Mitsuhashi, S, Iwama, K, Fujita, A, Imagawa, E, Alkanaq, AN, Koshimizu, E, Azuma, Y, Nakashima, M, Mizuguchi, T, Saitsu, H, Wada, Y, Minami, S, Katoh-Fukui, Y, Masunaga, Y, Fukami, M, Hasegawa, T, Ogata, T & Matsumoto, N 2019, 'MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: Bioinformatics consideration', Human molecular genetics, vol. 28, no. 14, ddz066, pp. 2319-2329. https://doi.org/10.1093/hmg/ddz066
Hamanaka K, Takata A, Uchiyama Y, Miyatake S, Miyake N, Mitsuhashi S et al. MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: Bioinformatics consideration. Human molecular genetics. 2019 Jul 15;28(14):2319-2329. ddz066. https://doi.org/10.1093/hmg/ddz066
Hamanaka, Kohei ; Takata, Atsushi ; Uchiyama, Yuri ; Miyatake, Satoko ; Miyake, Noriko ; Mitsuhashi, Satomi ; Iwama, Kazuhiro ; Fujita, Atsushi ; Imagawa, Eri ; Alkanaq, Ahmed N. ; Koshimizu, Eriko ; Azuma, Yoshiki ; Nakashima, Mitsuko ; Mizuguchi, Takeshi ; Saitsu, Hirotomo ; Wada, Yuka ; Minami, Sawako ; Katoh-Fukui, Yuko ; Masunaga, Yohei ; Fukami, Maki ; Hasegawa, Tomonobu ; Ogata, Tsutomu ; Matsumoto, Naomichi. / MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development : Bioinformatics consideration. In: Human molecular genetics. 2019 ; Vol. 28, No. 14. pp. 2319-2329.
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AU - Hamanaka, Kohei

AU - Takata, Atsushi

AU - Uchiyama, Yuri

AU - Miyatake, Satoko

AU - Miyake, Noriko

AU - Mitsuhashi, Satomi

AU - Iwama, Kazuhiro

AU - Fujita, Atsushi

AU - Imagawa, Eri

AU - Alkanaq, Ahmed N.

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AU - Saitsu, Hirotomo

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AU - Minami, Sawako

AU - Katoh-Fukui, Yuko

AU - Masunaga, Yohei

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AU - Matsumoto, Naomichi

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