title: Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome.
abstract: Acephalic spermatozoa syndrome is a rare and severe form of teratozoospermia characterized by a predominance of headless spermatozoa in the ejaculate. Family clustering and consanguinity suggest a genetic origin; however, causative mutations have yet to be identified. We performed whole-exome sequencing in two unrelated infertile men and subsequent variant filtering identified one homozygous (c.824C>T [p.Thr275Met]) and one compound heterozygous (c.1006C>T [p.Arg356Cys] and c.485T>A [p.Met162Lys]) SUN5 (also named TSARG4) variants. Sanger sequencing of SUN5 in 15 additional unrelated infertile men revealed four compound heterozygous (c.381delA [p.Val128Serfs∗7] and c.824C>T [p.Thr275Met]; c.381delA [p.Val128Serfs∗7] and c.781G>A [p.Val261Met]; c.216G>A [p.Trp72∗] and c.1043A>T [p.Asn348Ile]; c.425+1G>A/c.1043A>T [p.Asn348Ile]) and two homozygous (c.851C>G [p.Ser284∗]; c.350G>A [p.Gly114Arg]) variants in six individuals. These 10 SUN5 variants were found in 8 of 17 unrelated men, explaining the genetic defect in 47.06% of the affected individuals in our cohort. These variants were absent in 100 fertile population-matched control individuals. SUN5 variants lead to absent, significantly reduced, or truncated SUN5, and certain variants altered SUN5 distribution in the head-tail junction of the sperm. In summary, these results demonstrate that biallelic SUN5 mutations cause male infertility due to autosomal-recessive acephalic spermatozoa syndrome.
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Institute of Reproductive Genetics, Anhui Medical University, Hefei 230022, China; School of Life Science, Anhui Medical University, Hefei 230022, China. Electronic address: fxzhu@ahmu.edu.cn.
authors.forename: Fuxi
authors.initials: F
authors.lastname: Zhu
authors.affiliation: School of Life Science, Anhui Medical University, Hefei 230022, China.
authors.forename: Fengsong
authors.initials: F
authors.lastname: Wang
authors.affiliation: Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Institute of Reproductive Genetics, Anhui Medical University, Hefei 230022, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Institute of Reproductive Genetics, Anhui Medical University, Hefei 230022, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wu
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Institute of Reproductive Genetics, Anhui Medical University, Hefei 230022, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Institute of Reproductive Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Institute of Reproductive Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: He
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Institute of Reproductive Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Institute of Reproductive Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.
authors.forename: Zhaolian
authors.initials: Z
authors.lastname: Wei
authors.affiliation: School of Medicine, Robinson Research Institute, The University of Adelaide, and South Australian Health and Medical Research Institute, Adelaide, South Australia 5006, Australia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Institute of Reproductive Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China. Electronic address: caoyunxia6@126.com.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D003198:Computer Simulation; D059472:Exome / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D013094:Spermatozoa / Q000378:metabolism / Q000473:pathology*; D013577:Syndrome
chemical_list: D008565:Membrane Proteins; D011506:Proteins; C477147:SUN5 protein, human