@article{e4b9fc805d66467ea3e2c22726bb20f3,
title = "A homozygous FANCM frameshift pathogenic variant causes male infertility",
abstract = "Purpose: Fanconi anemia (FA) genes play important roles in spermatogenesis. In mice, disruption of Fancm impairs male fertility and testicular integrity, but whether FANCM pathogenic variants (PV) similarly affect fertility in men is unknown. Here we characterize a Pakistani family having three infertile brothers, two manifesting oligoasthenospermia and one exhibiting azoospermia, born to first-cousin parents. A homozygous PV in FANCM (c.1946_1958del, p.P648Lfs*16) was found cosegregating with male infertility. Our objective is to validate that FANCM p.P648Lfs*16 is the PV causing infertility in this family. Methods: Exome and Sanger sequencing were used for PV screening. DNA interstrand crosslink (ICL) sensitivity was assessed in lymphocytes from patients. A mouse model carrying a PV nearly equivalent to that in the patients (FancmΔC/ΔC) was generated, followed by functional analysis in spermatogenesis. Results: The loss-of-function FANCM PV increased ICL sensitivity in lymphocytes of patients and FancmΔC/ΔC spermatogonia. Adult FancmΔC/ΔC mice showed spermatogenic failure, with germ cell loss in 50.2% of testicular tubules and round-spermatid maturation arrest in 43.5% of tubules. In addition, neither bone marrow failure nor cancer/tumor was detected in all the patients or adult FancmΔC/ΔC mice. Conclusion: These findings revealed male infertility to be a novel phenotype of human patients with a biallelic FANCM PV.",
keywords = "FANCM PV, Interstrand crosslink sensitivity Fanconi anemia, Male infertility, Spermatogenic failure",
author = "Hao Yin and Hui Ma and Sajjad Hussain and Huan Zhang and Xuefeng Xie and Long Jiang and Xiaohua Jiang and Furhan Iqbal and Ihtisham Bukhari and Hanwei Jiang and Asim Ali and Liangwen Zhong and Tao Li and Suixing Fan and Beibei Zhang and Jianing Gao and Yang Li and Jabeen Nazish and Teka Khan and Manan Khan and Muhammad Zubair and Qiaomei Hao and Hui Fang and Jun Huang and Mahmoud Huleihel and Jiahao Sha and Pandita, {Tej K.} and Yuanwei Zhang and Qinghua Shi",
note = "Funding Information: We are grateful to the patients and their family members for providing information and materials. We thank the Fanconi Anemia Research Fund for the gift of anti-human FANCM antibodies, Prof. Maikun Teng (University of Science and Technology of China) for cDNA encoding human wild-type FANCM, Prof. Xingxu Huang (ShanghaiTech University) for pGL3-U6-sgRNA-PGK-puromycin plasmids, Prof. Chunsheng Han (Chinese Academy of Sciences) for anti-GFRA1 antibodies, Prof. Howard. J. Cooke (University of Edinburgh), Linyu Lu (Zhejiang University) and Zheng Wang (University of Southern California) for discussion, Prof. Feng Zhang (Fudan University) for his critical reading of the manuscript and expert advice, Cheng Yang (Anhui Medical University) for his expert advice, and Sigrid Eckardt for help with manuscript preparation. This work was supported by the Natural Science Foundation of China–Israel Science Foundation (31461143013, 313111245-1183/14), the National Key Research and Developmental Program of China (2016YFC1000605), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000), the National Basic Research Program of China (2014CB943101), the National Natural Science Foundation of China (31371519, 31501199, 31630050, 31601160, and 31571555), the Major Program of Development Foundation of Hefei Centre for Physical Science and Technology (2014FXZY003), and the Fundamental Research Funds for the Central Universities (WK2070000053 and WK2340000069). T.K.P. has been supported by National Institutes of Health grants CA129537 and GM109768. Publisher Copyright: {\textcopyright} 2018, The Author(s).",
year = "2019",
month = jan,
day = "1",
doi = "10.1038/s41436-018-0015-7",
language = "English (US)",
volume = "21",
pages = "62--70",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Elsevier B.V.",
number = "1",
}