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A homozygous FANCM frameshift pathogenic variant causes male infertility

Genetics in medicine, 2019-01, Vol.21 (1), p.62-70 [Tạp chí có phản biện]

2019 The Author(s) ;2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;The Author(s) 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;The Author(s) 2018 ;ISSN: 1098-3600 ;EISSN: 1530-0366 ;DOI: 10.1038/s41436-018-0015-7 ;PMID: 29895858

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Nhan đề:
A homozygous FANCM frameshift pathogenic variant causes male infertility
Tác giả: Yin, Hao ; Ma, Hui ; Hussain, Sajjad ; Zhang, Huan ; Xie, Xuefeng ; Jiang, Long ; Jiang, Xiaohua ; Iqbal, Furhan ; Bukhari, Ihtisham ; Jiang, Hanwei ; Ali, Asim ; Zhong, Liangwen ; Li, Tao ; Fan, Suixing ; Zhang, Beibei ; Gao, Jianing ; Li, Yang ; Nazish, Jabeen ; Khan, Teka ; Khan, Manan ; Zubair, Muhammad ; Hao, Qiaomei ; Fang, Hui ; Huang, Jun ; Huleihel, Mahmoud ; Sha, Jiahao ; Pandita, Tej K. ; Zhang, Yuanwei ; Shi, Qinghua
Chủ đề: Adult ; Animals ; DNA Helicases - genetics ; FANCM PV ; Fertility ; Frameshift Mutation ; Genetic Predisposition to Disease ; Homozygote ; Humans ; Infertility ; Infertility, Male - genetics ; Infertility, Male - pathology ; Interstrand crosslink sensitivity Fanconi anemia ; Loss of Function Mutation - genetics ; Male ; Male infertility ; Mice ; Oligospermia - genetics ; Oligospermia - pathology ; Pedigree ; Phenotype ; Spermatogenesis ; Spermatogenesis - genetics ; Spermatogenic failure ; Testis - pathology
Là 1 phần của: Genetics in medicine, 2019-01, Vol.21 (1), p.62-70
Mô tả: 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. 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. 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. These findings revealed male infertility to be a novel phenotype of human patients with a biallelic FANCM PV.
Nơi xuất bản: United States: Elsevier Inc
Ngôn ngữ: English
Số nhận dạng: ISSN: 1098-3600
EISSN: 1530-0366
DOI: 10.1038/s41436-018-0015-7
PMID: 29895858
Nguồn: MEDLINE
ProQuest Central

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A homozygous FANCM frameshift pathogenic variant causes male infertility

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