Bi‐allelic mutations in <scp><i>MCIDA</i>S</scp> and <scp><i>CCNO</i></scp> cause human infertility associated with abnormal gamete transport

Ma, Cong; Wu, Huan; Zhu, Damin; Wang, Ying; Shen, Qunshan; Cheng, Hongju; Zhang, Junqiang; Geng, Hao; Liu, Yiyuan; He, Xiaojin; Tao, Fangbiao; Cao, Yunxia; Xu, Xiaofeng

doi:10.1111/cge.14067

Cited by 8 publications

(6 citation statements)

References 37 publications

(58 reference statements)

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“…Thirty-seven publications reported on fertility outcomes in 119 women with PCD. Seventy-one women were subfertile ( Afzelius et al , 1978 ; Zhao et al , 2021 ; Afzelius and Eliasson, 1983 ; McComb et al , 1986 ; Greenstone et al , 1988 ; Lurie et al , 1989 ; Marchini et al , 1992 ; Halbert et al , 1997 ; Lin et al , 1998 ; McLean and Claman, 2000 ; Noone et al , 2004 ; Gavai et al , 2007 ; Ott et al , 2007 ; Abu-Musa et al , 2008 ; Plesec et al , 2008 ; Mishra et al , 2012 ; Chen et al , 2014 ; Onoufriadis et al , 2014 ; Imtiaz et al , 2015 ; Cao et al, 2016 ; Vanaken et al , 2017 ; Höben et al , 2018 ; Yang et al , 2018 ; Zhang et al , 2018 ; Yiallouros et al , 2019 ; Zhou et al , 2020 ; Akbarian et al , 2021 ; De Jesus-Rojas et al , 2021 ; Lu et al , 2021 ; Ma et al , 2021 ; Wang et al , 2021 ). Forty-eight women reported natural pregnancy ( Afzelius et al , 1978 ; Afzelius and Eliasson, 1983 ; Greenstone et al , 1988 ; Eliyahu and Shalev, 1996 ; Noone et al , 2004 ; Blyth and Wellesley, 2008 ; Onoufriadis et al , 2013 ; Marafie et al , 2015 ; Raidt et al , 2015 ; Cao et al, 2016 ; Cooley et al , 2016 ; Vanaken et al , 2017 ;…”

Section: Prevalence Of Subfertility In Women and Men With Pcdmentioning

confidence: 99%

“…This could lead to impaired sperm survival, impaired motility, and failure to navigate the female reproductive tract to achieve fertilization ( Berger et al , 2019 ). One case of PCD testicular biopsy demonstrated reduced quantities of ciliated cells within the efferent ductule, sperm agglutination, and ductal occlusion, whilst in another man with Kartagener syndrome, the efferent ductule cilia had absent dynein arms, providing further evidence for this theory ( Phillips et al , 1995 ; Ma et al , 2021 ). In addition, a study in mice with DNAH5 deficiency, which is associated with PCD in humans, demonstrated immotile efferent duct cilia with accumulation of sperm in the efferent duct whilst sperm ultrastructure and motility was unaffected ( Aprea et al , 2021 ).…”

Section: Possible Mechanisms By Which Pcd Causes Subfertilitymentioning

confidence: 99%

“…However, it is not clear if the remaining 16 ‘infertile’ women also underwent ART. Two cases which described embryo yield reported an average fertilization rate of 87% and an average of 56% viable embryos per oocyte retrieved ( Akbarian et al , 2021 ; Ma et al, 2021 ). Outcomes following ART use in males with PCD were reported in 65 cases, with ART leading to live births or ongoing pregnancy in 54 cases ( Table III ).…”

Section: Art Outcomes In Women and Men With Pcdmentioning

confidence: 99%

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The impact of primary ciliary dyskinesia on female and male fertility: a narrative review

Newman

Chopra

Dossett

et al. 2023

Human Reproduction Update

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BACKGROUND Primary ciliary dyskinesia (PCD) is a genetic condition affecting the structure and function of sperm flagellum and motile cilia including those in the male and female reproductive tracts. Infertility is a commonly reported feature of PCD, but there is uncertainty as to how best to counsel patients on their fertility prognosis. OBJECTIVE AND RATIONALE This review aimed to summarize the prevalence of subfertility, possible underlying mechanisms, and the success of ART in men and women with PCD. The efficacy of ART in this patient group is relatively unknown and, hence, the management of infertility in PCD patients remains a challenge. There are no previous published or registered systematic reviews of fertility outcomes in PCD. SEARCH METHODS Systematic literature searches were performed in Medline, Embase, Cochrane Library, and PubMed electronic databases to identify publications between 1964 and 2022 reporting fertility outcomes in men and women with PCD. Publications were excluded if they reported only animal studies, where gender was not specified or where subjects had a medical co-morbidity also known to impact fertility. Quality of evidence was assessed by critical appraisal and application of an appraisal tool for cross-sectional studies. The primary outcomes were natural conception in men and women with PCD, and conception following ART in men and women with PCD. OUTCOMES A total of 1565 publications were identified, and 108 publications were included after screening by two independent researchers. The quality of available evidence was low. The exact prevalence of subfertility in PCD is unclear but appears to be higher in men (up to 83% affected) compared to women (up to 61% affected). Variation in the prevalence of subfertility was observed between geographic populations which may be explained by differences in underlying genotype and cilia function. Limited evidence suggests subfertility in affected individuals is likely caused by abnormal cilia motion in the fallopian tubes, endometrium and efferent ductules, and dysmotile sperm. Some men and women with PCD benefited from ART, which suggests its use should be considered in the management of subfertility in this patient group. Further epidemiological and controlled studies are needed to determine the predictors of fertility and optimal management in this patient group. WIDER IMPLICATIONS It is important that patients with PCD receive evidence-based counselling about the potential impact of their condition on their fertility prognosis and what management options may be available to them if affected. Understanding the pathophysiology and optimal management of subfertility in PCD will increase our understanding of the role of cilia and the impact of wider secondary ciliopathies on reproduction.

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Section: Prevalence Of Subfertility In Women and Men With Pcdmentioning

confidence: 99%

Section: Possible Mechanisms By Which Pcd Causes Subfertilitymentioning

confidence: 99%

Section: Art Outcomes In Women and Men With Pcdmentioning

confidence: 99%

See 1 more Smart Citation

The impact of primary ciliary dyskinesia on female and male fertility: a narrative review

Newman

Chopra

Dossett

et al. 2023

Human Reproduction Update

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“…Normal ultrastructure and uncoordinated beat pattern in the residual cilia. Ma et al (2021) [ 22 ] 1 c.[262_263insGGCCC];[262_263insGGCCC], p.[Gln88Argfs*8];[Gln88Argfs*8]. Chronic airway infection, infertility.…”

Section: Tablementioning

confidence: 99%

Two Japanese Pediatric Patients With Primary Ciliary Dyskinesia Caused by Loss-of-Function Variants in the CCNO gene

Xu,

Ueda,

Nishikido

et al. 2024

Cureus

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Primary ciliary dyskinesia (PCD) is a rare congenital disorder caused by pathogenic variants of genes related to cilia. Here, we report two Japanese pediatric patients with PCD caused by pathogenic compound heterozygous variants in the cyclin O ( CCNO ) gene (Case 1, NM_021147.4:c.[262C>T];[781delC], p.[Gln88Ter];[Leu261fs]; Case 2, c.[262C>T];[c.248_252dupTGCCC], p.[Gln88Ter];[Gly85fs]). The clinical symptoms of the patients were varied. Neither of the patients had situs inversus. Transmission electron microscopy of the respiratory cilia from the nasal mucosa in Case 1 showed a remarkable reduction of cilia and the few residual cilia had central pair defects and microtubular disorganization.

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“…The contribution of Cyclin O (CCNO) -the first non-canonical cyclin expressed during this cell cycle variant- to MCC differentiation was first discovered in human patients with mutations in the CCNO gene. These patients suffer from a distinctive form of Primary Ciliary Dyskinesia (PCD) referred to as Reduced Generation of Multiple Motile cilia (RGMC) because of cilia rarity in the airway epithelium (Amirav et al, 2016; Casey et al, 2015; Guo et al, 2020; Henriques et al, 2021; Ma et al, 2021; Wallmeier et al, 2014). Tn parallel, an in-depth study of airway MCC from Cena mutant mice showed a disorganized ampliication of centrioles, ultimately resulting in incomplete multiciliation (Funk et al, 2015; Cena RA ).…”

Section: Introductionmentioning

confidence: 99%

Cyclin O controls entry into the cell-cycle variant required for multiciliated cell differentiation

Damaa,

Serizay,

Balagué

et al. 2024

Preprint

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Multiciliated cells (MCC) ensure proper fluid circulation in various organs in metazoans. Their differentiation is marked by the massive amplification of cilia-nucleating centrioles and is known to be controlled by various cell cycle components. In a companion study, we show that the differentiation of MCC is driven by a genuine cell-cycle variant characterized by sequential and wave-like expression of canonical and non-canonical cyclins such as Cyclin O (CCNO). Patients with CCNO mutations exhibit a subtype of Primary Ciliary Dyskinesia (PCD) designated as Reduced Generation of Multiple Motile Cilia (RGMC), yet the role of CCNO during MCC differentiation remains unclear. Here, using mice and human cellular models, single cell transcriptomics and functional studies, we show that Ccno is activated during a strategic temporal window at the crossroads between the onset of MCC differentiation, the entry into the MCC cell cycle variant, and the activation of the centriole biogenesis program. We find that the absence of Ccno leads to a block of MCC progenitor differen- tiation at the G1/S-like transition, just before the beginning of centriole formation. This leads to a complete lack of centrioles and cilia in mouse brain and human airway MCC. Altogether, our study identifies CCNO as a core regulator of entry into the MCC cell cycle variant and shows that the coupling of centriole biogenesis to an S-like phase, maintained in MCC, is dependent on CCNO.

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Bi‐allelic mutations in MCIDAS and CCNO cause human infertility associated with abnormal gamete transport

Cited by 8 publications

References 37 publications

The impact of primary ciliary dyskinesia on female and male fertility: a narrative review

The impact of primary ciliary dyskinesia on female and male fertility: a narrative review

Two Japanese Pediatric Patients With Primary Ciliary Dyskinesia Caused by Loss-of-Function Variants in the CCNO gene

Cyclin O controls entry into the cell-cycle variant required for multiciliated cell differentiation

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