Bi-allelic variants in DNAH10 cause asthenoteratozoospermia and male infertility

Li, Kuokuo; Wang, Guanxiong; Lv, Mingrong; Wang, Jieyu; Gao, Yang; Tang, Feng; Xu, Chuan; Yang, Wen Bin; Yu, Hui; Shao, Zhongmei; Geng, Hao; Tan, Qing; Shen, Qunshan; Tang, Dongdong; Ni, Xiaoqing; Wang, Tianjuan; Song, Bing; Wu, Huan; Huo, Ran; Zhang, Zhiguo; Xu, Yuping; Zhou, Ping; Tao, Fangbiao; Wei, Zhaolian; He, Xiaojin; Cao, Yunxia

doi:10.1007/s10815-021-02306-x

Cited by 19 publications

(19 citation statements)

References 33 publications

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“…This type of male infertility was consistent with that described in previous studies. 17 Moreover, the ultrastructural and immunofluorescence analyses of the sperm samples revealed severe defects in the mitochondria. Previous studies in animal models have suggested that TBC1D21 is crucial for mitochondrial and axoneme development in mammalian sperm through interaction with TOMM20 and DNAH7.…”

Section: Discussionmentioning

confidence: 99%

Loss of function mutation in DNAH7 induces male infertility associated with abnormalities of the sperm flagella and mitochondria in human

et al. 2022

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Male infertility is an increasingly serious health problem affecting couples of reproductive age. Mutations in axoneme-associated genes cause male infertility. Dynein arm proteins are essential in sustaining normal axonemes and promote flagellar motility. However, the function of DNAH7 in male fertility in vivo remains unclear. Herein, we showed that DNAH7 disruption in humans results in male infertility, which was characterised by multiple morphological abnormalities of sperm flagella. The axoneme structure of the sperm from a DNAH7-deficient patient revealed the loss of inner dynein arms. Moreover, the mitochondria of the sperm flagella detached and dispersed outside the axoneme, leading to abnormalities in the mitochondrial sheath in the mid-piece region. Live birth was achieved via intracytoplasmic sperm injection. Thus, DNAH7 is critical for axoneme and mitochondrial development in human sperm. These findings further clarify the spectrum of DNAH7 biology and provide new insights for diagnosing infertility and treating patients harbouring DNAH7 mutations.

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Section: Discussionmentioning

confidence: 99%

Loss of function mutation in DNAH7 induces male infertility associated with abnormalities of the sperm flagella and mitochondria in human

et al. 2022

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“…Both study groups recruited males with MMAF and performed whole-exome sequencing. 45,46 Tu et al found five case subjects who had rare, deleterious variants in the DNAH10 gene. Two of the men were homozygous carriers, and the rest three were compound heterozygous carriers for variants in the gene of interest.…”

Section: Dnah10mentioning

confidence: 99%

“…45 Li et al reported one invididual who carried a homozygous frameshift variant and another one who was compound heterozygous for variants in the DNAH10 gene. 46 Both research groups found that the axoneme of the carriers of variants in the DNAH10 gene showed an abnormal structure-the inner dynein arms were missing. Moreover, the DNAH10 protein was substantially reduced in the sperm samples of the individuals harboring these variants compared to the controls.…”

Section: Dnah10mentioning

confidence: 99%

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Potential role of dynein‐related genes in the etiology of male infertility: A systematic review and a meta‐analysis

2022

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Background The dynein‐related genes may have a role in the etiology of male infertility, particularly in cases of impaired sperm motility. Objectives The goal of this review is to compile a list of the most important dynein‐related candidate genes that may contribute to male factor infertility. Materials and methods Databases were searched using the keywords “dynein,” “male,” “infertility,” and by applying strict inclusion criteria. A meta‐analysis was also performed by using the eligible case‐control studies. The odd ratios (ORs), the Z‐test score, and the level of significance were determined using a fixed model with a p value of 0.05. Funnel plots were used to check for publication bias. Results There were 35 studies that met the inclusion criteria. There were a total of 15 genes responsible for the production of dynein structural proteins, the production of dynein assembling factors, and potentially associated with male infertility. A total of five case‐control studies were eligible for inclusion in the meta‐analysis. Variants in the dynein‐related genes were linked to an increased the risk of male infertility (OR = 21.52, 95% confidence interval 8.34–55.50, Z test = 6.35, p < 0.05). The percentage of heterogeneity, I2, was 47.00%. The lack of variants in the dynein genes was an advantage, and this was statistically significant. Discussion The results from the present review illustrate that pathogenic variants in genes both for dynein synthesis and for dynein assembly factors could be associated with isolated cases of male infertility without any other symptoms. Conclusions The genes addressed in this study, which are involved in both the production and assembly of dynein, could be used as molecular targets for future research into the etiology of sperm motility problems.

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“…Genetic origin accounts for 35–60% of these MMAF cases. Several gene-families are identified as associated with flagella, including the AKAP family, DANI family, DNAH family, RSPH family, CCDC family, CFAP family, TTC family, and some single genes [ 1 , 9 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ].…”

Section: Introductionmentioning

confidence: 99%

LRRC46 Accumulates at the Midpiece of Sperm Flagella and Is Essential for Spermiogenesis and Male Fertility in Mouse

Yin

et al. 2022

IJMS

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The sperm flagellum is essential for male fertility. Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. MMAF phenotypes are understood to result from pathogenic variants of genes from multiple families including AKAP, DANI, DNAH, RSPH, CCDC, CFAP, TTC, and LRRC, among others. The Leucine-rich repeat protein (LRRC) family includes two members reported to cause MMAF phenotypes: Lrrc6 and Lrrc50. Despite vigorous research towards understanding the pathogenesis of MMAF-related diseases, many genes remain unknown underlying the flagellum biogenesis. Here, we found that Leucine-rich repeat containing 46 (LRRC46) is specifically expressed in the testes of adult mice, and show that LRRC46 is essential for sperm flagellum biogenesis. Both scanning electron microscopy (SEM) and Papanicolaou staining (PS) presents that the knockout of Lrrc46 in mice resulted in typical MMAF phenotypes, including sperm with short, coiled, and irregular flagella. The male KO mice had reduced total sperm counts, impaired sperm motility, and were completely infertile. No reproductive phenotypes were detected in Lrrc46−/−female mice. Immunofluorescence (IF) assays showed that LRRC46 was present throughout the entire flagella of control sperm, albeit with evident concentration at the mid-piece. Transmission electron microscopy (TEM) demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. About the important part of the Materials and Methods, SEM and PS were used to observe the typical MMAF-related irregular flagella morphological phenotypes, TEM was used to further inspect the sperm flagellum defects in ultrastructure, and IF was chosen to confirm the location of protein. Our study suggests that LRRC46 is an essential protein for sperm flagellum biogenesis, and its mutations might be associated with MMAF that causes male infertility. Thus, our study provides insights for understanding developmental processes underlying sperm flagellum formation and contribute to further observe the pathogenic genes that cause male infertility.

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Bi-allelic variants in DNAH10 cause asthenoteratozoospermia and male infertility

Cited by 19 publications

References 33 publications

Loss of function mutation in DNAH7 induces male infertility associated with abnormalities of the sperm flagella and mitochondria in human

Loss of function mutation in DNAH7 induces male infertility associated with abnormalities of the sperm flagella and mitochondria in human

Potential role of dynein‐related genes in the etiology of male infertility: A systematic review and a meta‐analysis

LRRC46 Accumulates at the Midpiece of Sperm Flagella and Is Essential for Spermiogenesis and Male Fertility in Mouse

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