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Year : 2022  |  Volume : 24  |  Issue : 3  |  Page : 229-230

“Progressive motility” in elucidating novel genetic causes of male infertility

Institute of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai 201203, China

Date of Submission01-Apr-2022
Date of Acceptance02-Apr-2022
Date of Web Publication22-Apr-2022

Correspondence Address:
Feng Zhang
Institute of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011; State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438; Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai 201203
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aja202231

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How to cite this article:
Zhang F. “Progressive motility” in elucidating novel genetic causes of male infertility. Asian J Androl 2022;24:229-30

How to cite this URL:
Zhang F. “Progressive motility” in elucidating novel genetic causes of male infertility. Asian J Androl [serial online] 2022 [cited 2022 Sep 27];24:229-30. Available from:

Feng Zhang
Guest Editor for this special issue.

Genetic factors play important roles in the etiology of male infertility. The routine clinical genetic testing for human spermatogenic failure is currently limited to abnormal karyotypes (e.g., 47,XXY for Klinefelter syndrome) and Y chromosomal microdeletions.[1] However, these chromosomal variants only account for approximately 20% of the infertile males with nonobstructive azoospermia. The vast majority of male infertile cases are genetically unexplained.[1] With the recent advances in genomic technologies, the genome-wide dissections at the nucleotide resolution have been achieved, and the novel genetic factors involved in human male infertility have been continuously uncovered. Furthermore, the methodological progresses in gene manipulation (e.g., clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 [CRISPR/Cas9]) and animal modeling facilitate functional verifications for the genetic etiology of male infertility. This special issue, “Genetics of Male Infertility”, contains two reviews, five original articles, and one commentary to introduce some recent research progresses in the genetic field of male infertility.

Due to the high genetic heterogeneity, there are plenty of unknown genetic causes to be elucidated for male infertility. Uncovering these missing genetic etiologies was previously technically challenging. Because of the natural purifying selection on human infertility, these infertility-associated genetic variants could be extremely rare in human populations. Therefore, it is difficult for the candidate gene-based sequencing strategy to identify recurrently mutated genes based on a small sample size of male infertile cases. With the advances in genomic technologies, genetic variants in the protein-coding regions of all the human genes can be efficiently analyzed in a single test via whole-exome sequencing (WES).[2] This technology has been widely used in the genetic studies of human male infertility, especially teratozoospermia affecting the sperm head, tail (flagellum), and the coupling apparatus between them. Wang et al.[3] systematically review the genetic pathogenesis of acephalic spermatozoa syndrome (ASS), which is caused by the defects in sperm head–tail coupling apparatus. At least seven genes have been identified as the causal genes responsible for ASS, and SUN5 (Sad1 and UNC84 domain containing 5) and PMFBP1 (polyamine-modulated factor 1 binding protein 1) are the most significant genes contributing to ASS.[3]

Sperm tail malformation, also known as multiple morphological abnormalities of the flagella (MMAF), is another hot field of male infertility. More than half of the MMAF cases can be genetically explained by the genes uncovered during the past 8 years.[4] Here, Zubair et al.[5] conducted WES and identified a homozygous missense variant of CCDC103 (coiled-coil domain containing 103) in two infertile brothers with severe sperm mid-piece and tail abnormalities. This study also expands the phenotype spectrum of CCDC103. Furthermore, Man et al.[6] systematically review and introduce the molecular functions of intraflagellar transport protein 25 (IFT25) and its interactions with other IFT particle subunits during flagellogenesis.

Genetic defects also affect sperm head. After conducting WES for a case with severe oligozoospermia and macrozoospermia, Kherraf et al.[7] identified a homozygous frameshift variant in ZMYND15 (zinc finger MYND-type containing 15), a previously known gene associated with nonobstructive azoospermia. Since AURKC (aurora kinase C) defect is the major cause of macrozoospermia, Kherraf et al.[7] recommended the direct use of WES to discover genetic causes for the macrozoospermia cases with negative AURKC diagnosis. In a previous study by Xin et al.[8], WES helped the identification of a homozygous missense mutation of ACTL7A (actin-like protein 7A) in two infertile brothers with acrosomal ultrastructural defects. In a recent study on ACTL7A, Yang et al.[9] further showed that ACTL7A is a promising biomarker for fertilization outcomes of assisted reproductive technology.

WES has been an efficient genetic method to identify causal genetic variants in male infertility. However, small deletions and duplications cannot be readily ascertained by WES; moreover, most of noncoding variants are beyond the coverage of WES. Therefore, further genetic analyses are needed for the WES-negative cases. Array-based comparative genomic hybridization can reliably identify deletions and duplication in coding and noncoding regions of the human genome,[10] but this technology is not applicable for balanced structural variants. Here, Chau et al.[11] conducted low-pass mate-pair genome sequencing for the cases with male infertility and revealed genomic structural variants with truncating breakpoints in spermatogenesis-associated genes and potential noncoding regulatory elements/domains.

Technical advances in DNA sequencing did help the efficient discovery of novel genetic factors in male infertility. But, the human variant evidence alone is not sufficient to confirm the causal relationship between a specific gene and male infertility. Gene manipulation in animal models is a frequently used strategy for further functional and mechanistic investigations on pathogenic variants. Thanks to the technical advances in gene manipulation, such as CRISPR/Cas9,[12] gene knock-out and knock-in can be efficiently achieved in mouse models. Since most of the spermatogenesis-related genes are predominantly or specifically expressed in the testis, no conditional knock-out is needed when generating mouse models for male infertility; a regular gene manipulation assay is applicable when functionally verifying the identified novel genes in human infertile males.[3],[4],[8],[10] Furthermore, Oyama et al.[13] have conducted CRISPR/Cas9-mediated editing in mice and showed that some testis-enriched genes are dispensable for male fertility. As for this phenomenon, Houston[14] has highlighted the potential contributions of environmental factors and gene–environment interactions to the phenotypic variances between human cases and animal models.

As highlighted in this special issue, rapid progresses in the genome technologies and animal models have provided a better understanding of the genetic etiology of male infertility. For some specific subtypes (e.g., MMAF) of male infertility, most of the human cases can be genetically explained, which further facilitate the genetic diagnosis and personalize treatment for the monogenic male infertility. Furthermore, recent progresses in medical genetics also revealed gene–gene interactions and some multilocus variant combinations in manifesting clinical phenotypes.[15] When genetic diagnosis can not be achieved based on the variants at a single locus, their contributions to male infertility cannot be readily excluded. Double or triple, or more hits in different testis-enriched genes may still be involved in male infertility. Therefore, for the male infertile cases negative for any single gene diagnosis, multilocus integrated analysis may be a solution in the future studies of male infertility.

  References Top

Houston BJ, Riera-Escamilla A, Wyrwoll MJ, Salas-Huetos A, Xavier MJ, et al. A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships. Hum Reprod Update 2021; 28: 15–29.  Back to cited text no. 1
Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, et al. Exome sequencing identifies the cause of a Mendelian disorder. Nat Genet 2010; 42: 30–5.  Back to cited text no. 2
Wang Y, Xiang MF, Zheng N, Cao YX, Zhu FX. Genetic pathogenesis of acephalic spermatozoa syndrome: past, present, and future. Asian J Androl 2022; 24: 231–7.  Back to cited text no. 3
Toure A, Martinez G, Kherraf ZE, Cazin C, Beurois J, et al. The genetic architecture of morphological abnormalities of the sperm tail. Hum Genet 2021; 140: 21–42.  Back to cited text no. 4
Zubair M, Khan R, Ma A, Hameed U, Khan M, et al. A recurrent homozygous missense mutation in CCDC103 causes asthenoteratozoospermia due to disorganized dynein arms. Asian J Androl 2022; 24: 255–9.  Back to cited text no. 5
Man YH, Warmbrunn I, Zhang L, Zhang ZB. The roles of intraflagellar transport (IFT) protein 25 in mammalian signaling transduction and flagellogenesis. Asian J Androl 2021; 24: 238–42.  Back to cited text no. 6
Kherraf ZE, Cazin C, Lestrade F, Muronova J, Coutton C, et al. From azoospermia to macrozoospermia, a phenotypic continuum due to mutations in the ZMYND15 gene. Asian J Androl 2022; 24: 243–7.  Back to cited text no. 7
Xin A, Qu R, Chen G, Zhang L, Chen J, et al. Disruption in ACTL7A causes acrosomal ultrastructural defects in human and mouse sperm as a novel male factor inducing early embryonic arrest. Sci Adv 2020; 6: eaaz4796.  Back to cited text no. 8
Yang TY, Chen Y, Chen GW, Sun YS, Li ZC, et al. Sperm-specific protein ACTL7A as a biomarker for fertilization outcomes of assisted reproductive technology. Asian J Androl 2022; 24: 260–5.  Back to cited text no. 9
Tang S, Wang X, Li W, Yang X, Li Z, et al. Biallelic mutations in CFAP43 and CFAP44 cause male infertility with multiple morphological abnormalities of the sperm flagella. Am J Hum Genet 2017; 100: 854–64.  Back to cited text no. 10
Chau MHK, Li Y, Dai P, Shi M, Zhu X, et al. Investigation of the genetic etiology in male infertility with apparently balanced chromosomal structural rearrangements by genome sequencing. Asian J Androl 2022; 24: 248–54.  Back to cited text no. 11
Cong L, Ran FA, Cox D, Lin S, Barretto R, et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013; 339: 819–23.  Back to cited text no. 12
Oyama Y, Miyata H, Shimada K, Fujihara Y, Tokuhiro K, et al. CRISPR/Cas9-mediated genome editing reveals 12 testis-enriched genes dispensable for male fertility in mice. Asian J Androl 2021; 24: 266–72.  Back to cited text no. 13
Houston BJ. Commentary on “CRISPR/Cas9-mediated genome editing reveals 12 testis-enriched genes dispensable for male fertility in mice”. Asian J Androl 2021; 24: 273.  Back to cited text no. 14
Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med 2017; 376: 21–31.  Back to cited text no. 15


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