Novel variants in DNAH9 lead to nonsyndromic severe asthenozoospermia

Tang, Dongdong; Sha, Yanwei; Gao, Yang; Zhang, Jingjing; Cheng, Hongju; Zhang, Junqiang; Ni, Xiaoqing; Wang, Chao; Xu, Chuan; Geng, Hao; He, Xiaojin; Cao, Yunxia

doi:10.1186/s12958-021-00709-0

Cited by 22 publications

(12 citation statements)

References 27 publications

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“…Furthermore, mutations in DNAH1 , DNAH2 , DNAH8 , and DNAH17 have been shown to cause predominant male infertility, although mild PCD symptoms may be present [ 13 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. Interestingly, asthenospermia without PCD symptoms was recently reported in two patients with DNAH9 mutations [ 50 ]. DNAH9 is a known PCD gene, which is required for distal ODA assembly in motile cilia and causes mild PCD symptoms [ 51 , 52 ].…”

Section: Role Of Pcd Genes In Male Fertilitymentioning

confidence: 99%

“…Similar estimates were reported for MMAF patients: 63–68%, 54–57%, and 43% for fertilization, pregnancy, and live birth rates, respectively [ 66 , 96 ]. Successful clinical pregnancies by various methods have been reported for couples with male partner PCD [ 57 , 61 , 62 , 83 , 84 , 85 , 86 , 97 , 98 , 99 , 100 , 101 ] and for some known PCD genes [ 50 , 66 , 102 , 103 , 104 ], as summarized in Table 3 .…”

Section: Success Of Art In Pcd Patientsmentioning

confidence: 99%

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Diagnostics and Management of Male Infertility in Primary Ciliary Dyskinesia

Jayasena

Sironen

2021

Diagnostics

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Primary ciliary dyskinesia (PCD), a disease caused by the malfunction of motile cilia, manifests mainly with chronic recurrent respiratory infections. In men, PCD is also often associated with infertility due to immotile sperm. Since causative mutations for PCD were identified in over 50 genes, the role of these genes in sperm development should be investigated in order to understand the effect of PCD mutations on male fertility. Previous studies showed that different dynein arm heavy chains are present in respiratory cilia and sperm flagellum, which may partially explain the variable effects of mutations on airways and fertility. Furthermore, recent studies showed that male reproductive tract motile cilia may play an important part in sperm maturation and transport. In some PCD patients, extremely low sperm counts were reported, which may be due to motile cilia dysfunction in the reproductive tract rather than problems with sperm development. However, the exact roles of PCD genes in male fertility require additional studies, as do the treatment options. In this review, we discuss the diagnostic and treatment options for men with PCD based on the current knowledge.

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Section: Role Of Pcd Genes In Male Fertilitymentioning

confidence: 99%

Section: Success Of Art In Pcd Patientsmentioning

confidence: 99%

Diagnostics and Management of Male Infertility in Primary Ciliary Dyskinesia

Jayasena

Sironen

2021

Diagnostics

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“…For instance, the DANH1 gene is a candidate gene for PCD, which encodes a core component of inner-arm heavy chain dynein, and an investigation carried out by Sha et al [ 24 ] demonstrated that 12 patients harboring DNAH1 variants only presented the MMAF phenotype in the absence of PCD-related symptoms. DNAH9 is another candidate gene for PCD, but Tang et al [ 25 ] reported that DNAH9 variants can result in non-syndromic severe asthenospermia without PCD-related symptoms. Based on this, MMAF may be another form of classical PCD [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF

Tang

Shao

et al. 2022

Reprod Biol Endocrinol

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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 (5th 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.

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“…and DNAH17 (Asai & Wilkes, 2004). To date, biallelic variants in ten of these, DNAH1 (Wang et al, 2017), DNAH2 (Hwang et al, 2021), DNAH5-11 (He et al, 2020;Li et al, 2022;Liu et al, 2020;Oud et al, 2021;Tang et al, 2021;Wei et al, 2021;Zhu et al, 2019), and DNAH17 (Zhang et al, 2020) have been reported to be associated with human male infertility and asthenozoospermia.…”

Section: Discussionmentioning

confidence: 99%

Novel compound heterozygous variants of DNAH17 in a Chinese infertile man with multiple morphological abnormalities of sperm flagella

Liu

Wang

Feng³

et al. 2022

Andrologia

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Multiple morphological abnormalities of the sperm flagellum (MMAF) have been reported to be an important cause of male infertility and reflect a heterogeneous genetic disorder. Previous studies have identified dozens of candidate pathogenic genes for MMAF, but the aetiology in approximately 50% of cases remains unexplained. The present study aimed to identify novel potentially pathogenic gene variants of MMAF. A Chinese family with a 32‐year‐old infertile proband presenting with MMAF was recruited, and sperm morphology of the patient was examined by Papanicolaou staining. Whole exome sequencing was performed on the proband and Sanger sequencing was used to identify genetic variants in the family. The frequencies of variants were assessed using public databases and the effects on protein structure and function were predicted by online bioinformatics tools. The patient exhibited asthenozoospermia and a MMAF phenotype. Novel compound heterozygous variants (c.5368C > T, p.R1790C and c.13183C > T, p.R4395W) of the DNAH17 gene were identified in the patient, and showed autosomal recessive inheritance in this family. These variants were very rare in the GnomAD database. The two mutated amino acids were located in a highly conserved region of the DNAH17 protein. In silico analysis revealed that the compound heterozygous variants may compromise the function of DNAH17. Our findings expand upon the spectrum of pathogenic DNAH17 variants that are responsible for MMAF, and provide new knowledge for genetic counselling of male infertility due to MMAF.

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Novel variants in DNAH9 lead to nonsyndromic severe asthenozoospermia

Cited by 22 publications

References 27 publications

Diagnostics and Management of Male Infertility in Primary Ciliary Dyskinesia

Diagnostics and Management of Male Infertility in Primary Ciliary Dyskinesia

Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF

Novel compound heterozygous variants of DNAH17 in a Chinese infertile man with multiple morphological abnormalities of sperm flagella

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