研究開発・学会発表
診療・治療
Rare TUBB8B Missense Variants as Potential Contributors to Unexplained Infertility and Early Pregnancy Loss
- ASPIRE 2026
- Beijing, Cnina
- Rare TUBB8B Missense Variants as Potential Contributors to Unexplained Infertility and Early Pregnancy Loss
- Xingqiang Wei1), Junko Otsuki1,2), Naoto Mukaida1), Miki Fujii1), Kaori Kodera1), Ai Yamada1), Nao Hayashi1), Yihsien Enatsu1), Kunihiro Enatsu1), Noritoshi Enatsu1), Yoko Tokura1), Satoshi Yamada1), Yuri Mizusawa1), Eri Okamoto1), Shoji Kokeguchi1), Hayato Asama3), Daigaku Kamibayashi3), Toshiroh Iwasaki1), Mikiya Nakatsuka2), and Masahide Shiotani1)
1) Hanabusa Women’s Clinic, 1-1-2 Sannomiya, Chuo-ku, Kobe, Hyogo 650-0021, Japan
2) Faculty of Health Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, Okayama 700-8558, Japan
3)Kanazawa Tamago Clinic, 327-1 Nakachou, Moroemachi, Kanazawa, Ishikawa, 920-0016, Japan
Background and Objective:
Tubulin β-isotypes play essential roles in meiotic spindle assembly during oocyte maturation. Pathogenic variants in TUBB8 are well established causes of oocyte maturation arrest and fertilization failure; however, the physiological function of its paralog TUBB8B remains unknown, and no clinical reports have described its potential involvement in human reproductive disorders. This study aimed to identify rare TUBB8B variants in women with unexplained infertility or recurrent pregnancy loss (RPL) and to characterize their genetic and evolutionary features.
Methods:
This study analyzed a whole-exome sequencing (WES) cohort of 58 Japanese women previously described by our group, supplemented with additional participants. The cohort included individuals with repeated ART failure, RPL, ART-derived live births, and natural conceptions. Variants in TUBB8B were screened using nested PCR followed by Sanger sequencing. Evolutionary conservation was evaluated by multispecies alignment, and variant positions were mapped onto predicted protein domains. Population allele frequencies were obtained from TOPMed and 38KJPN databases.
Results:
Two rare heterozygous missense variants, p.Pro261Arg (rs736027734) and p.Met403Val (rs758328960), were identified in unrelated women with long-standing infertility and ≥20 unsuccessful ART cycles. Both individuals experienced early miscarriages after biochemical pregnancies. Both variants affected evolutionarily conserved amino acids, and structural mapping localized p.Pro261Arg within the Tubulin_C domain and p.Met403Val adjacent to a predicted coiled-coil region. The variants were extremely rare or rare in population databases and were undetectable by prior WES analysis but confirmed by nested PCR/Sanger sequencing. No TUBB8B variants were found in women with live births.
Conclusion:
This study provides the first clinical evidence that rare TUBB8B missense variants may contribute to unexplained infertility and RPL. These findings highlight TUBB8B as a potential candidate gene in human reproductive failure and reveal important limitations of WES in detecting tubulin gene family variants.
