Rare mutations in the complement regulatory gene CSMD1 are associated with male and female infertility

Arthur S. Lee; Jannette Rusch; Ana C. Lima; Abul Usmani; Ni Huang; Maarja Lepamets; Katinka A. Vigh-Conrad; Ronald E. Worthington; Reedik Mägi; Xiaobo Wu; Kenneth I. Aston; John P. Atkinson; Douglas T. Carrell; Rex A. Hess; Moira K. O’Bryan; Donald F. Conrad

doi:10.1038/s41467-019-12522-w

Rare mutations in the complement regulatory gene CSMD1 are associated with male and female infertility

Arthur S. Lee, Jannette Rusch, Ana C. Lima, Abul Usmani, Ni Huang, Maarja Lepamets, Katinka A. Vigh-Conrad, Ronald E. Worthington, Reedik Mägi, Xiaobo Wu, Kenneth I. Aston, John P. Atkinson, Douglas T. Carrell, Rex A. Hess, Moira K. O’Bryan, Donald F. Conrad

Oregon National Primate Research Center

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

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.

Original language	English (US)
Article number	4626
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12522-w
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Lee, A. S., Rusch, J., Lima, A. C., Usmani, A., Huang, N., Lepamets, M., Vigh-Conrad, K. A., Worthington, R. E., Mägi, R., Wu, X., Aston, K. I., Atkinson, J. P., Carrell, D. T., Hess, R. A., O’Bryan, M. K., & Conrad, D. F. (2019). Rare mutations in the complement regulatory gene CSMD1 are associated with male and female infertility. Nature communications, 10(1), Article 4626. https://doi.org/10.1038/s41467-019-12522-w

Lee, AS, Rusch, J, Lima, AC, Usmani, A, Huang, N, Lepamets, M, Vigh-Conrad, KA, Worthington, RE, Mägi, R, Wu, X, Aston, KI, Atkinson, JP, Carrell, DT, Hess, RA, O’Bryan, MK & Conrad, DF 2019, 'Rare mutations in the complement regulatory gene CSMD1 are associated with male and female infertility', Nature communications, vol. 10, no. 1, 4626. https://doi.org/10.1038/s41467-019-12522-w

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abstract = "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.",

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Rare mutations in the complement regulatory gene CSMD1 are associated with male and female infertility

Abstract

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