Wen-Bin He1, Juan Du1, Xiao-Wen Yang2, Wen Li1, Wei-Lin Tang3, Can Dai4, Yong-Zhe Chen2, Ya-Xin Zhang2, Guang-Xiu Lu1, Ge Lin5, Fei Gong6, Yue-Qiu Tan7. 1. Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, People's Republic of China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan 410078, People's Republic of China; NHC Key Laboratory of human stem cell and reproductive engineering, Changsha, Hunan 410078, People's Republic of China. 2. Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, People's Republic of China. 3. Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan 410078, People's Republic of China. 4. Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan 410078, People's Republic of China; School of Medicine, Hunan Normal University, Changsha, Hunan 410013, People's Republic of China. 5. Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, People's Republic of China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan 410078, People's Republic of China; NHC Key Laboratory of human stem cell and reproductive engineering, Changsha, Hunan 410078, People's Republic of China; School of Medicine, Hunan Normal University, Changsha, Hunan 410013, People's Republic of China. 6. Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, People's Republic of China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan 410078, People's Republic of China; NHC Key Laboratory of human stem cell and reproductive engineering, Changsha, Hunan 410078, People's Republic of China. Electronic address: gfdirector@126.com. 7. Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, People's Republic of China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan 410078, People's Republic of China; NHC Key Laboratory of human stem cell and reproductive engineering, Changsha, Hunan 410078, People's Republic of China. Electronic address: tanyueqiu@csu.edu.cn.
Abstract
RESEARCH QUESTION: What is the genetic aetiology of three resistant ovary syndrome (ROS) pedigrees from 13 Chinese Han families with non-syndromic premature ovarian insufficiency (POI). DESIGN: The proband in each family was subjected to whole-exome sequencing. Bioinformatic and in-vitro functional analyses were performed for the functional characterization of the FSHR mutations. RESULTS: Four novel mutations, two homozygous mutations (c.419delA, c.1510C>T), and a compound heterozygous mutation (c.44G>A and deletion of exons 1 and 2) of FSHR were identified in the three non-syndromic POI-with-ROS families. Bioinformatic analysis predicted that the three novel point mutations in FSHR are deleterious and associated with POI in the three families, which was confirmed by in-vitro functional analysis, in which FSH-induced adenosine 3',5'-cyclic monophosphate production was abolished for all receptors. CONCLUSIONS: The three novel point mutations in FSHR were all functional inactivating mutations, and were the genetic aetiology of the three non-syndromic POI-with-ROS families. The first FSHR frameshift mutation is reported here, and the first missense mutation in the signal peptide-encoding region of FSHR to be associated with POI. Women affected by ROS should consider undergoing mutation screening for FSHR.
RESEARCH QUESTION: What is the genetic aetiology of three resistant ovary syndrome (ROS) pedigrees from 13 Chinese Han families with non-syndromic premature ovarian insufficiency (POI). DESIGN: The proband in each family was subjected to whole-exome sequencing. Bioinformatic and in-vitro functional analyses were performed for the functional characterization of the FSHR mutations. RESULTS: Four novel mutations, two homozygous mutations (c.419delA, c.1510C>T), and a compound heterozygous mutation (c.44G>A and deletion of exons 1 and 2) of FSHR were identified in the three non-syndromic POI-with-ROS families. Bioinformatic analysis predicted that the three novel point mutations in FSHR are deleterious and associated with POI in the three families, which was confirmed by in-vitro functional analysis, in which FSH-induced adenosine 3',5'-cyclic monophosphate production was abolished for all receptors. CONCLUSIONS: The three novel point mutations in FSHR were all functional inactivating mutations, and were the genetic aetiology of the three non-syndromic POI-with-ROS families. The first FSHR frameshift mutation is reported here, and the first missense mutation in the signal peptide-encoding region of FSHR to be associated with POI. Women affected by ROS should consider undergoing mutation screening for FSHR.
Authors: Asma Sassi; Julie Désir; Véronique Janssens; Martina Marangoni; Dorien Daneels; Alexander Gheldof; Maryse Bonduelle; Sonia Van Dooren; Sabine Costagliola; Anne Delbaere Journal: F S Rep Date: 2020-08-22