CSB-PGBD3 Mutations Cause Premature Ovarian Failure

Yingying Qin; Ting Guo; Guangyu Li; Tie-Shan Tang; Shidou Zhao; Xue Jiao; Juanjuan Gong; Fei Gao; Caixia Guo; Joe Leigh Simpson; Zi-Jiang Chen

doi:10.1371/journal.pgen.1005419

CSB-PGBD3 Mutations Cause Premature Ovarian Failure

PLoS Genet. 2015 Jul 28;11(7):e1005419. doi: 10.1371/journal.pgen.1005419. eCollection 2015 Jul.

Authors

Yingying Qin¹, Ting Guo¹, Guangyu Li¹, Tie-Shan Tang², Shidou Zhao¹, Xue Jiao¹, Juanjuan Gong², Fei Gao³, Caixia Guo⁴, Joe Leigh Simpson⁵, Zi-Jiang Chen⁶

Affiliations

¹ Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China.
² State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
³ State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
⁴ Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
⁵ Research and Global Programs March of Dimes Foundation, White Plains, New York, United States of America.
⁶ Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China; Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Premature ovarian failure (POF) is a rare, heterogeneous disorder characterized by cessation of menstruation occurring before the age of 40 years. Genetic etiology is responsible for perhaps 25% of cases, but most cases are sporadic and unexplained. In this study, through whole exome sequencing in a non-consanguineous family having four affected members with POF and Sanger sequencing in 432 sporadic cases, we identified three novel mutations in the fusion gene CSB-PGBD3. Subsequently functional studies suggest that mutated CSB-PGBD3 fusion protein was impaired in response to DNA damage, as indicated by delayed or absent recruitment to damaged sites. Our data provide the first evidence that mutations in the CSB-PGBD3 fusion protein can cause human disease, even in the presence of functional CSB, thus potentially explaining conservation of the fusion protein for 43 My since marmoset. The localization of the CSB-PGBD3 fusion protein to UVA-induced nuclear DNA repair foci further suggests that the CSB-PGBD3 fusion protein, like many other proteins that can cause POF, modulates or participates in DNA repair.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Base Sequence
Cell Line, Tumor
Cockayne Syndrome / genetics
DNA Damage / genetics
DNA Helicases / genetics*
DNA Repair / genetics*
DNA Repair Enzymes / genetics*
Female
HEK293 Cells
HeLa Cells
Humans
Menopause, Premature / genetics*
Middle Aged
Mutant Chimeric Proteins / genetics*
Poly-ADP-Ribose Binding Proteins
Primary Ovarian Insufficiency / genetics*
Recombinant Fusion Proteins / genetics
Sequence Analysis, DNA

Substances

Mutant Chimeric Proteins
Poly-ADP-Ribose Binding Proteins
Recombinant Fusion Proteins
CSB-PGBD3 fusion protein, human
DNA Helicases
ERCC6 protein, human
DNA Repair Enzymes

Grants and funding

This work was supported by the National Basic Research Program of China (973 program-2012CB944700 to ZJC); the National Natural Science Foundation of China (81270662, 81471509 to YQ); the Key Program of National Natural Science Foundation of China (81430029 to ZJC); and Program for New Century Excellent Talents in University (NCET-12-0334 to YQ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.