RT Journal Article
SR Electronic
T1 The complement system supports normal postnatal development and gonadal function in both sexes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 233825
DO 10.1101/233825
A1 Arthur S. Lee
A1 Jannette Rusch
A1 Abul Usmani
A1 Ana C. Lima
A1 Wendy S.W. Wong
A1 Ni Huang
A1 Maarja Lepamets
A1 Katinka A. Vigh-Conrad
A1 Ronald E. Worthington
A1 Reedik Mägi
A1 John E. Niederhuber
A1 Xiaobo Wu
A1 John P. Atkinson
A1 Rex A. Hess
A1 Donald F. Conrad
YR 2017
UL http://biorxiv.org/content/early/2017/12/14/233825.abstract
AB 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.