TY - JOUR
T1 - Rare mutations in the complement regulatory gene CSMD1 are associated with male and female infertility
AU - Lee, Arthur S.
AU - Rusch, Jannette
AU - Lima, Ana C.
AU - Usmani, Abul
AU - Huang, Ni
AU - Lepamets, Maarja
AU - Vigh-Conrad, Katinka A.
AU - Worthington, Ronald E.
AU - Mägi, Reedik
AU - Wu, Xiaobo
AU - Aston, Kenneth I.
AU - Atkinson, John P.
AU - Carrell, Douglas T.
AU - Hess, Rex A.
AU - O’Bryan, Moira K.
AU - Conrad, Donald F.
N1 - Funding Information:
We thank all patients and study participants. D.F.C is supported by the National Institutes of Health (R01HD078641 and R01MH101810). A.S.L. was supported by a Distinguished Scholar Award from Washington University School of Medicine. A.C.L. was supported by a fellowship from the Lalor Foundation. We thank Heather Lawson for training and consultation on animal husbandry. We thank Brianne Tabers for technical assistance with animal husbandry. We thank Anne O’Connor and Jo Merriner for performing histology on testis samples, and helpful discussions. We thank Kelle Moley and members of her laboratory (Praba Esakky, Michaela Reid, and Jessica Saben) for consultations on tissue preparations. We thank Tim Schedl, Matt Baum, and Nicole Rockweiler for helpful discussions. We thank Nicholas Ho for technical assistance with image quantification. We thank Seungeun Lee for discussion of SKAT results. We thank Bill Eades and Chris Holley at the Washington University Siteman Flow Cytometry Core (NCI P30 CA91842) FACS services. We thank the Washington University Rheumatic Disease Core (NIHP30AR48335) for providing backcrossed mouse genotypes. We thank the University of Virginia Ligand Assay and Analysis Core (U54 DH28934) for hormone measurements. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. This paper was not prepared in collaboration with investigators of the WHI, has not been reviewed and/or approved by the Women’s Health Initiative (WHI), and does not necessarily reflect the opinions of the WHI investigators or the NHLBI. Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278. The Women’s Health Initiative Sequencing Project (WHISP) was funded by Grant Number RC2 HL102924. This study used data from the NHLBI Grand Opportunity Exome Sequencing Project (GOESP). Funding for GO-ESP was provided by NHLBI grants RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Infertility in men and women is a complex genetic trait with shared biological bases between the sexes. Here, we perform a series of rare variant analyses across 73,185 women and men to identify genes that contribute to primary gonadal dysfunction. We report CSMD1, a complement regulatory protein on chromosome 8p23, as a strong candidate locus in both sexes. We show that CSMD1 is enriched at the germ-cell/somatic-cell interface in both male and female gonads. Csmd1-knockout males show increased rates of infertility with significantly increased complement C3 protein deposition in the testes, accompanied by severe histological degeneration. Knockout females show significant reduction in ovarian quality and breeding success, as well as mammary branching impairment. Double knockout of Csmd1 and C3 causes non-additive reduction in breeding success, suggesting that CSMD1 and the complement pathway play an important role in the normal postnatal development of the gonads in both sexes.
AB - Infertility in men and women is a complex genetic trait with shared biological bases between the sexes. Here, we perform a series of rare variant analyses across 73,185 women and men to identify genes that contribute to primary gonadal dysfunction. We report CSMD1, a complement regulatory protein on chromosome 8p23, as a strong candidate locus in both sexes. We show that CSMD1 is enriched at the germ-cell/somatic-cell interface in both male and female gonads. Csmd1-knockout males show increased rates of infertility with significantly increased complement C3 protein deposition in the testes, accompanied by severe histological degeneration. Knockout females show significant reduction in ovarian quality and breeding success, as well as mammary branching impairment. Double knockout of Csmd1 and C3 causes non-additive reduction in breeding success, suggesting that CSMD1 and the complement pathway play an important role in the normal postnatal development of the gonads in both sexes.
UR - http://www.scopus.com/inward/record.url?scp=85073176208&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12522-w
DO - 10.1038/s41467-019-12522-w
M3 - Article
C2 - 31604923
AN - SCOPUS:85073176208
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4626
ER -