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The complement system supports normal postnatal development and gonadal function in both sexes

View ORCID ProfileArthur Lee, Jannette Rusch, Abul Usmani, Ana Lima, Wendy Wong, Ni Huang, Maarja Lepamets, Katinka Vigh-Conrad, Ronald Worthington, Reedik Magi, John Niederhuber, Xiaobo Wu, John Atkinson, Rex Hess, View ORCID ProfileDonald Conrad
doi: https://doi.org/10.1101/233825
Arthur Lee
Washington University School of Medicine;
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Jannette Rusch
Washington University School of Medicine;
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Abul Usmani
Washington University School of Medicine;
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Ana Lima
Washington University School of Medicine;
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Wendy Wong
Inova Health System;
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Ni Huang
Washington University School of Medicine;
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Maarja Lepamets
University of Tartu;
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Katinka Vigh-Conrad
Washington University School of Medicine;
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Ronald Worthington
Southern Illinois University at Edwardsville;
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Reedik Magi
University of Tartu;
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John Niederhuber
Inova Health Systems;
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Xiaobo Wu
Washington University School of Medicine;
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John Atkinson
Washington University School of Medicine;
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Rex Hess
University of Illinois at Urbana Champaign
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Donald Conrad
Washington University School of Medicine;
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  • For correspondence: don.conrad@wustl.edu
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Abstract

Male and female infertility are clinically managed and classified as distinct diseases, and relatively little is known about mechanisms of gonadal function common to both sexes. We used genome-wide genetic analysis on 74,896 women and men to find rare genetic variants that modulate gonadal function in both sexes. This uncovered an association with variants disrupting CSMD1, a complement regulatory protein located on 8p23, in a genomic region with an exceptional evolution. We found that Csmd1 knockout mice display a diverse array of gonadal defects in both sexes, and in females, impaired mammary gland development that leads to increased offspring mortality. The complement pathway is significantly disrupted in Csmd1 mice, and further disruption of the complement pathway from joint inactivation of C3 leads to more extreme reproductive defects. Our results can explain a novel human genetic association with infertility and implicate the complement system in the normal development of postnatal tissues.

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The copyright holder for this preprint is the author/funder. It is made available under a CC-BY 4.0 International license.
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  • Posted December 14, 2017.

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The complement system supports normal postnatal development and gonadal function in both sexes
Arthur Lee, Jannette Rusch, Abul Usmani, Ana Lima, Wendy Wong, Ni Huang, Maarja Lepamets, Katinka Vigh-Conrad, Ronald Worthington, Reedik Magi, John Niederhuber, Xiaobo Wu, John Atkinson, Rex Hess, Donald Conrad
bioRxiv 233825; doi: https://doi.org/10.1101/233825
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The complement system supports normal postnatal development and gonadal function in both sexes
Arthur Lee, Jannette Rusch, Abul Usmani, Ana Lima, Wendy Wong, Ni Huang, Maarja Lepamets, Katinka Vigh-Conrad, Ronald Worthington, Reedik Magi, John Niederhuber, Xiaobo Wu, John Atkinson, Rex Hess, Donald Conrad
bioRxiv 233825; doi: https://doi.org/10.1101/233825

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