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Homozygous mutation in SLO3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations
BACKGROUND: Potassium channels are important for the structure and function of the spermatozoa. As a potassium transporter, the mSlo3 is essential for male fertility as Slo3 knockout male mice were infertile with the series of functional defects in sperm cells. However, no pathogenic variant has bee...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722334/ https://www.ncbi.nlm.nih.gov/pubmed/34980136 http://dx.doi.org/10.1186/s12958-021-00880-4 |
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author | Lv, Mingrong Liu, Chunyu Ma, Chunjie Yu, Hui Shao, Zhongmei Gao, Yang Liu, Yiyuan Wu, Huan Tang, Dongdong Tan, Qing Zhang, Junqiang Li, Kuokuo Xu, Chuan Geng, Hao Zhang, Jingjing Li, Hang Mao, Xiaohong Ge, Lei Fu, Feifei Zhong, Kaixin Xu, Yuping Tao, Fangbiao Zhou, Ping Wei, Zhaolian He, Xiaojin Zhang, Feng Cao, Yunxia |
author_facet | Lv, Mingrong Liu, Chunyu Ma, Chunjie Yu, Hui Shao, Zhongmei Gao, Yang Liu, Yiyuan Wu, Huan Tang, Dongdong Tan, Qing Zhang, Junqiang Li, Kuokuo Xu, Chuan Geng, Hao Zhang, Jingjing Li, Hang Mao, Xiaohong Ge, Lei Fu, Feifei Zhong, Kaixin Xu, Yuping Tao, Fangbiao Zhou, Ping Wei, Zhaolian He, Xiaojin Zhang, Feng Cao, Yunxia |
author_sort | Lv, Mingrong |
collection | PubMed |
description | BACKGROUND: Potassium channels are important for the structure and function of the spermatozoa. As a potassium transporter, the mSlo3 is essential for male fertility as Slo3 knockout male mice were infertile with the series of functional defects in sperm cells. However, no pathogenic variant has been detected in human SLO3 to date. Here we reported a human case with homozygous SLO3 mutation. The function of SLO3 in human sperm and the corresponding assisted reproductive strategy are also investigated. METHODS: We performed whole-exome sequencing analysis from a large cohort of 105 patients with asthenoteratozoospermia. The effects of the variant were investigated by quantitative RT-PCR, western blotting, and immunofluorescence assays using the patient spermatozoa. Sperm morphological and ultrastructural studies were conducted using haematoxylin and eosin staining, scanning and transmission electron microscopy. RESULTS: We identified a homozygous missense variant (c.1237A > T: p.Ile413Phe) in the sperm-specific SLO3 in one Chinese patient with male infertility. This SLO3 variant was rare in human control populations and predicted to be deleterious by multiple bioinformatic tools. Sperm from the individual harbouring the homozygous SLO3 variant exhibited severe morphological abnormalities, such as acrosome hypoplasia, disruption of the mitochondrial sheath, coiled tails, and motility defects. The levels of SLO3 mRNA and protein in spermatozoa from the affected individual were reduced. Furthermore, the acrosome reaction, mitochondrial membrane potential, and membrane potential during capacitation were also afflicted. The levels of acrosome marker glycoproteins and PLCζ1 as well as the mitochondrial sheath protein HSP60 and SLO3 auxiliary subunit LRRC52, were significantly reduced in the spermatozoa from the affected individual. The affected man was sterile due to acrosome and mitochondrial dysfunction; however, intra-cytoplasmic sperm injection successfully rescued this infertile condition. CONCLUSIONS: SLO3 deficiency seriously impact acrosome formation, mitochondrial sheath assembly, and the function of K(+) channels. Our findings provided clinical implications for the genetic and reproductive counselling of affected families. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12958-021-00880-4. |
format | Online Article Text |
id | pubmed-8722334 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-87223342022-01-06 Homozygous mutation in SLO3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations Lv, Mingrong Liu, Chunyu Ma, Chunjie Yu, Hui Shao, Zhongmei Gao, Yang Liu, Yiyuan Wu, Huan Tang, Dongdong Tan, Qing Zhang, Junqiang Li, Kuokuo Xu, Chuan Geng, Hao Zhang, Jingjing Li, Hang Mao, Xiaohong Ge, Lei Fu, Feifei Zhong, Kaixin Xu, Yuping Tao, Fangbiao Zhou, Ping Wei, Zhaolian He, Xiaojin Zhang, Feng Cao, Yunxia Reprod Biol Endocrinol Research BACKGROUND: Potassium channels are important for the structure and function of the spermatozoa. As a potassium transporter, the mSlo3 is essential for male fertility as Slo3 knockout male mice were infertile with the series of functional defects in sperm cells. However, no pathogenic variant has been detected in human SLO3 to date. Here we reported a human case with homozygous SLO3 mutation. The function of SLO3 in human sperm and the corresponding assisted reproductive strategy are also investigated. METHODS: We performed whole-exome sequencing analysis from a large cohort of 105 patients with asthenoteratozoospermia. The effects of the variant were investigated by quantitative RT-PCR, western blotting, and immunofluorescence assays using the patient spermatozoa. Sperm morphological and ultrastructural studies were conducted using haematoxylin and eosin staining, scanning and transmission electron microscopy. RESULTS: We identified a homozygous missense variant (c.1237A > T: p.Ile413Phe) in the sperm-specific SLO3 in one Chinese patient with male infertility. This SLO3 variant was rare in human control populations and predicted to be deleterious by multiple bioinformatic tools. Sperm from the individual harbouring the homozygous SLO3 variant exhibited severe morphological abnormalities, such as acrosome hypoplasia, disruption of the mitochondrial sheath, coiled tails, and motility defects. The levels of SLO3 mRNA and protein in spermatozoa from the affected individual were reduced. Furthermore, the acrosome reaction, mitochondrial membrane potential, and membrane potential during capacitation were also afflicted. The levels of acrosome marker glycoproteins and PLCζ1 as well as the mitochondrial sheath protein HSP60 and SLO3 auxiliary subunit LRRC52, were significantly reduced in the spermatozoa from the affected individual. The affected man was sterile due to acrosome and mitochondrial dysfunction; however, intra-cytoplasmic sperm injection successfully rescued this infertile condition. CONCLUSIONS: SLO3 deficiency seriously impact acrosome formation, mitochondrial sheath assembly, and the function of K(+) channels. Our findings provided clinical implications for the genetic and reproductive counselling of affected families. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12958-021-00880-4. BioMed Central 2022-01-03 /pmc/articles/PMC8722334/ /pubmed/34980136 http://dx.doi.org/10.1186/s12958-021-00880-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Lv, Mingrong Liu, Chunyu Ma, Chunjie Yu, Hui Shao, Zhongmei Gao, Yang Liu, Yiyuan Wu, Huan Tang, Dongdong Tan, Qing Zhang, Junqiang Li, Kuokuo Xu, Chuan Geng, Hao Zhang, Jingjing Li, Hang Mao, Xiaohong Ge, Lei Fu, Feifei Zhong, Kaixin Xu, Yuping Tao, Fangbiao Zhou, Ping Wei, Zhaolian He, Xiaojin Zhang, Feng Cao, Yunxia Homozygous mutation in SLO3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations |
title | Homozygous mutation in SLO3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations |
title_full | Homozygous mutation in SLO3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations |
title_fullStr | Homozygous mutation in SLO3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations |
title_full_unstemmed | Homozygous mutation in SLO3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations |
title_short | Homozygous mutation in SLO3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations |
title_sort | homozygous mutation in slo3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722334/ https://www.ncbi.nlm.nih.gov/pubmed/34980136 http://dx.doi.org/10.1186/s12958-021-00880-4 |
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