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Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF
BACKGROUND: Multiple morphological abnormalities of the sperm flagella (MMAF) is a subtype of severe asthenoteratozoospermia with poorly understood genetic etiology. SPAG6 is a core axonemal component that plays a critical role in the formation of cilia and sperm flagella. Previous studies have repo...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886842/ https://www.ncbi.nlm.nih.gov/pubmed/35232447 http://dx.doi.org/10.1186/s12958-022-00916-3 |
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author | Xu, Chuan Tang, Dongdong Shao, Zhongmei Geng, Hao Gao, Yang Li, Kuokuo Tan, Qing Wang, Guanxiong Wang, Chao Wu, Huan Li, Guanjian Lv, Mingrong He, Xiaojin Cao, Yunxia |
author_facet | Xu, Chuan Tang, Dongdong Shao, Zhongmei Geng, Hao Gao, Yang Li, Kuokuo Tan, Qing Wang, Guanxiong Wang, Chao Wu, Huan Li, Guanjian Lv, Mingrong He, Xiaojin Cao, Yunxia |
author_sort | Xu, Chuan |
collection | PubMed |
description | BACKGROUND: Multiple morphological abnormalities of the sperm flagella (MMAF) is a subtype of severe asthenoteratozoospermia with poorly understood genetic etiology. SPAG6 is a core axonemal component that plays a critical role in the formation of cilia and sperm flagella. Previous studies have reported that mutations in SPAG6 cause primary ciliary dyskinesia (PCD), but the association between SPAG6 gene variants and the MMAF phenotype has not yet been described. METHODS: We performed whole-exome sequencing (WES) in two unrelated Han Chinese men with MMAF. Sanger sequencing was used to validate the candidate variants. Routine semen analysis was carried out according to the WHO guidelines (5(th) Edition). Sperm morphology was assessed using modified Papanicolaou staining. Scanning and transmission electron microscopy (S/TEM) was performed to observe the ultrastructural defects of the sperm flagella. Western blot analysis and immunofluorescence (IF) of spermatozoa were performed to examine the expression of SPAG6 protein. Assisted fertilization with intracytoplasmic sperm injection (ICSI) was applied. RESULTS: Two homozygous SPAG6 variants were identified by WES and Sanger validation in two patients with MMAF phenotype (F1 II-1: c.308C > A, p. A103D; F2 II-1: c. 585delA, p. K196Sfs*6). Semen analysis showed progressive rates of less than 1%, and most of the spermatozoa presented MMAF by Papanicolaou staining. TEM revealed that the overall axonemal ultrastructure was disrupted and primarily presented an abnormal “9 + 0” configuration. No other PCD-related symptoms were found on physical examination and medical consultations, as well as lung CT screening. The level of SPAG6 protein was significantly decreased in the spermatozoa, and IF analysis revealed that SPAG6 staining was extremely weak and discontinuous in the sperm flagella of the two patients. Notably, F1 II-1 and his wife conceived successfully after undergoing ICSI. CONCLUSIONS: Our research provides new evidence for a potential correlation between SPAG6 variants and the MMAF phenotype. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12958-022-00916-3. |
format | Online Article Text |
id | pubmed-8886842 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-88868422022-03-17 Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF Xu, Chuan Tang, Dongdong Shao, Zhongmei Geng, Hao Gao, Yang Li, Kuokuo Tan, Qing Wang, Guanxiong Wang, Chao Wu, Huan Li, Guanjian Lv, Mingrong He, Xiaojin Cao, Yunxia Reprod Biol Endocrinol Research BACKGROUND: Multiple morphological abnormalities of the sperm flagella (MMAF) is a subtype of severe asthenoteratozoospermia with poorly understood genetic etiology. SPAG6 is a core axonemal component that plays a critical role in the formation of cilia and sperm flagella. Previous studies have reported that mutations in SPAG6 cause primary ciliary dyskinesia (PCD), but the association between SPAG6 gene variants and the MMAF phenotype has not yet been described. METHODS: We performed whole-exome sequencing (WES) in two unrelated Han Chinese men with MMAF. Sanger sequencing was used to validate the candidate variants. Routine semen analysis was carried out according to the WHO guidelines (5(th) Edition). Sperm morphology was assessed using modified Papanicolaou staining. Scanning and transmission electron microscopy (S/TEM) was performed to observe the ultrastructural defects of the sperm flagella. Western blot analysis and immunofluorescence (IF) of spermatozoa were performed to examine the expression of SPAG6 protein. Assisted fertilization with intracytoplasmic sperm injection (ICSI) was applied. RESULTS: Two homozygous SPAG6 variants were identified by WES and Sanger validation in two patients with MMAF phenotype (F1 II-1: c.308C > A, p. A103D; F2 II-1: c. 585delA, p. K196Sfs*6). Semen analysis showed progressive rates of less than 1%, and most of the spermatozoa presented MMAF by Papanicolaou staining. TEM revealed that the overall axonemal ultrastructure was disrupted and primarily presented an abnormal “9 + 0” configuration. No other PCD-related symptoms were found on physical examination and medical consultations, as well as lung CT screening. The level of SPAG6 protein was significantly decreased in the spermatozoa, and IF analysis revealed that SPAG6 staining was extremely weak and discontinuous in the sperm flagella of the two patients. Notably, F1 II-1 and his wife conceived successfully after undergoing ICSI. CONCLUSIONS: Our research provides new evidence for a potential correlation between SPAG6 variants and the MMAF phenotype. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12958-022-00916-3. BioMed Central 2022-03-01 /pmc/articles/PMC8886842/ /pubmed/35232447 http://dx.doi.org/10.1186/s12958-022-00916-3 Text en © The Author(s) 2022 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 Xu, Chuan Tang, Dongdong Shao, Zhongmei Geng, Hao Gao, Yang Li, Kuokuo Tan, Qing Wang, Guanxiong Wang, Chao Wu, Huan Li, Guanjian Lv, Mingrong He, Xiaojin Cao, Yunxia Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF |
title | Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF |
title_full | Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF |
title_fullStr | Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF |
title_full_unstemmed | Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF |
title_short | Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF |
title_sort | homozygous spag6 variants can induce nonsyndromic asthenoteratozoospermia with severe mmaf |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886842/ https://www.ncbi.nlm.nih.gov/pubmed/35232447 http://dx.doi.org/10.1186/s12958-022-00916-3 |
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