Yaqian Li1, Chuan Jiang1, Xueguang Zhang1, Mohan Liu1, Yongkang Sun1, Yihong Yang2, Ying Shen3. 1. Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. 2. Reproduction Medical Center of West China Second University Hospital, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, 610041, China. yyhpumc@foxmail.com. 3. Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. yingcaishen01@163.com.
Abstract
PURPOSE: There are limited genes known to cause primary ciliary dyskinesia (PCD)-associated asthenozoospermia. In the present study, we aimed to expand the spectrum of mutations in PCD and to provide new information for genetic counseling diagnoses and the treatment of male infertility in PCD. METHODS: One sterile patient with typical situs inversus was recruited to our center, and semen sample was collected. We performed whole-exome sequencing (WES) on the patient to identify the pathogenic mutations associated with PCD and used transmission electron microscopy to investigate spermatozoal ultrastructure. In addition, western blotting and immunofluorescence staining were used to confirm the untoward impact of the variant on the expression of LRRC6, as well as on the dynein arm proteins in the patient's spermatozoa. RESULTS: We identified a homozygous nonsense variant c.749G>A (p.W250*) of LRRC6 in the PCD patient. This variant severely impaired LRRC6 expression and further led to negative effects on dynein arm protein expression in the spermatozoa of the affected individual, which eventually caused defects in sperm ultrastructure and motility. Moreover, we are the first to report a positive prognosis using intracytoplasmic sperm injection (ICSI) for LRRC6-associated male infertility. CONCLUSIONS: Our findings strongly implicated the homozygous mutation of c.749G>A (p.W250*) in LRRC6 as a new genetic cause of PCD, uncovering its involvement in defective sperm flagella and poor sperm motility. Furthermore, we posit that patients with LRRC6 mutations may have good outcomes with ICSI treatment. These findings add to the literature on the genetic diagnoses and treatment of male infertility associated with PCD.
PURPOSE: There are limited genes known to cause primary ciliary dyskinesia (PCD)-associated asthenozoospermia. In the present study, we aimed to expand the spectrum of mutations in PCD and to provide new information for genetic counseling diagnoses and the treatment of male infertility in PCD. METHODS: One sterile patient with typical situs inversus was recruited to our center, and semen sample was collected. We performed whole-exome sequencing (WES) on the patient to identify the pathogenic mutations associated with PCD and used transmission electron microscopy to investigate spermatozoal ultrastructure. In addition, western blotting and immunofluorescence staining were used to confirm the untoward impact of the variant on the expression of LRRC6, as well as on the dynein arm proteins in the patient's spermatozoa. RESULTS: We identified a homozygous nonsense variant c.749G>A (p.W250*) of LRRC6 in the PCD patient. This variant severely impaired LRRC6 expression and further led to negative effects on dynein arm protein expression in the spermatozoa of the affected individual, which eventually caused defects in sperm ultrastructure and motility. Moreover, we are the first to report a positive prognosis using intracytoplasmic sperm injection (ICSI) for LRRC6-associated male infertility. CONCLUSIONS: Our findings strongly implicated the homozygous mutation of c.749G>A (p.W250*) in LRRC6 as a new genetic cause of PCD, uncovering its involvement in defective sperm flagella and poor sperm motility. Furthermore, we posit that patients with LRRC6 mutations may have good outcomes with ICSI treatment. These findings add to the literature on the genetic diagnoses and treatment of male infertility associated with PCD.
Authors: Johanna Raidt; Julia Wallmeier; Rim Hjeij; Jörg Große Onnebrink; Petra Pennekamp; Niki T Loges; Heike Olbrich; Karsten Häffner; Gerard W Dougherty; Heymut Omran; Claudius Werner Journal: Eur Respir J Date: 2014-09-03 Impact factor: 16.671
Authors: Adam J Shapiro; Stephanie D Davis; Deepika Polineni; Michele Manion; Margaret Rosenfeld; Sharon D Dell; Mark A Chilvers; Thomas W Ferkol; Maimoona A Zariwala; Scott D Sagel; Maureen Josephson; Lucy Morgan; Ozge Yilmaz; Kenneth N Olivier; Carlos Milla; Jessica E Pittman; M Leigh Anne Daniels; Marcus Herbert Jones; Ibrahim A Janahi; Stephanie M Ware; Sam J Daniel; Matthew L Cooper; Lawrence M Nogee; Billy Anton; Tori Eastvold; Lynn Ehrne; Elena Guadagno; Michael R Knowles; Margaret W Leigh; Valery Lavergne Journal: Am J Respir Crit Care Med Date: 2018-06-15 Impact factor: 21.405
Authors: Peadar G Noone; Margaret W Leigh; Aruna Sannuti; Susan L Minnix; Johnny L Carson; Milan Hazucha; Maimoona A Zariwala; Michael R Knowles Journal: Am J Respir Crit Care Med Date: 2003-12-04 Impact factor: 21.405
Authors: Amjad Horani; Thomas W Ferkol; David Shoseyov; Mollie G Wasserman; Yifat S Oren; Batsheva Kerem; Israel Amirav; Malena Cohen-Cymberknoh; Susan K Dutcher; Steven L Brody; Orly Elpeleg; Eitan Kerem Journal: PLoS One Date: 2013-03-19 Impact factor: 3.240
Authors: Bryony Braschi; Heymut Omran; George B Witman; Gregory J Pazour; K Kevin Pfister; Elspeth A Bruford; Stephen M King Journal: J Cell Biol Date: 2022-01-10 Impact factor: 8.077