Ultrastructural Sperm Flagellum Defects in a Patient With CCDC39 Compound Heterozygous Mutations and Primary Ciliary Dyskinesia/Situs Viscerum Inversus

Cannarella, Rossella; Maniscalchi, Eugenia Tiziana; Condorelli, Rosita A.; Scalia, Marina; Vignera, Sandro La; Bertelli, Matteo; Calogero, Aldo E.

doi:10.3389/fgene.2020.00974

Cited by 9 publications

(3 citation statements)

References 37 publications

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“…Mutations in just one of the over 600 proteins in a motile cilium can result in severe motility defects or paralysis (Bower et al, 2018;Urbanska et al, 2018;Urbanska et al, 2015). In humans, ciliary defects can lead to numerous diseases -called ciliopathies -including primary ciliary dyskinesia (Hjeij et al, 2014;Wirschell et al, 2011;Yamamoto et al, 2013), situs inversus (Cannarella et al, 2020;Matwijiw et al, 1987), male infertility (Coutton et al, 2018), and polycystic kidney disease (Huang and Lipschutz, 2014).…”

Section: Introductionmentioning

confidence: 99%

Cryo-electron tomography of eel sperm flagella reveals a molecular “minimum system” for motile cilia

Schrad

Hable

et al. 2023

Preprint

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Cilia and flagella play a crucial role in the development and function of most eukaryotic organisms. The structural core of the flagellum, the axoneme, is conserved in most eukaryotes and careful regulation of dynein motors within the axoneme is required for proper ciliary beating. The sperm flagellum from the American eel (Anguilla rostrata) has been shown to lack many of the canonical axonemal proteins, including the radial spokes, the central pair complex, and possibly even the outer row of dynein arms, presenting a 'minimal' flagellar system. Here, we present cryo-electron tomography analysis of the eel sperm flagellum. We identified two states for the eel sperm flagellum within our tomograms, narrow and wide, and found that the flagellum started narrow near the sperm head and widened distally. Subtomogram averages revealed that the eel sperm flagellum has retained remnants of the missing regulatory complexes, including a short radial spoke 3 complex, basal components of radial spokes 1 and 2, and an outer dynein arm docking complex. We also describe unique structural features of the A. rostrata sperm flagellum, such as a unique pattern of holes at the inner junction and an accessory complex located at the 'outer' junction. Finally, we discuss the consequences of losing key regulatory factors for the eel sperm flagellum and hypothesize several evolutionary factors that may have led to their loss. Together, our results shed light onto the structure and function of the eel sperm axoneme and provide insight into the minimum requirements for proper ciliary beating.

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Section: Introductionmentioning

confidence: 99%

Cryo-electron tomography of eel sperm flagella reveals a molecular “minimum system” for motile cilia

Schrad

Hable

et al. 2023

Preprint

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“…Variations in the genes related to the development and function of nodal cilia often lead to human laterality defects. Up to now, more than 82 genes have been reported to be related to LR asymmetry disorders, including cilia-and flagella-associated protein family members, coiled-coil domain-containing family members, dynein axonemal assembly factors, dynein axonemal light chains, dynein axonemal intermediate chains, and dynein axonemal heavy chains (DNAHs) (Osório et al, 2019;Al Mutairi et al, 2020;Bustamante-Marin et al, 2020a;Bustamante-Marin et al, 2020b;Cannarella et al, 2020;Chen et al, 2020;Cho et al, 2020;Ding et al, 2020;Heigwer et al, 2020;Sahabian et al, 2020;Sha et al, 2020a;Thomas et al, 2020;Wang et al, 2020;Yang and Qi, 2020;Abdelhamed et al, 2021;Derrick et al, 2021;Guo et al, 2021;Wang et al, 2021). Genes belonging to the DNAH family, such as DNAH1 (OMIM 603332), DNAH5 (OMIM 603335), DNAH6 (OMIM 603336), DNAH9 (OMIM 603330), and DNAH11 (OMIM 603339), are reported to be closely associated with cilia and/or flagella beating (Fliegauf et al, 2005;Hornef et al, 2006;Pifferi et al, 2010;Li et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Identification of DNAH17 Variants in Han-Chinese Patients With Left–Right Asymmetry Disorders

Yuan

Deng

et al. 2022

Front. Genet.

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The formation of left–right asymmetry of the visceral organs is a conserved feature of the human body, and the asymmetry specification of structure and function is precisely orchestrated by multiple regulatory mechanisms. The abnormal results of organ positioning situs arise from defective cilia structure or function during embryogenesis in humans. In this study, we recruited two unrelated Han-Chinese families with left–right asymmetry disorders. The combination of whole-exome sequencing and Sanger sequencing identified two compound heterozygous variants: c.4109C>T and c.9776C>T, and c.612C>G and c.8764C>T in the dynein axonemal heavy chain 17 gene (DNAH17) in two probands with left–right asymmetry disorders. We report for the first time a possible association between DNAH17 gene variants and left–right asymmetry disorders, which is known as a causal gene for asthenozoospermia. Altogether, the findings of our study may enlarge the DNAH17 gene variant spectrum in human left–right asymmetry disorders, pave a way to illustrate the potential pathogenesis of ciliary/flagellar disorders, and provide supplementary explanation for genetic counseling.

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“…Primary ciliary dyskinesia (PCD, OMIM#244400) is a rare and recessively inherited disorder caused by defects in the structure or function of cilia ( 1 – 3 ). Approximately 1 in 10,000–20,000 individuals suffer from this syndrome worldwide, and the prevalence of PCD is high in highly consanguineous communities ( 2 , 4 , 5 ). Because of the wide distribution of cilia, PCD can involve multiple organs or systems and greatly impacts the patients' quality of life ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Biallelic Variants in CCDC39 Gene Lead to Primary Ciliary Dyskinesia and Kartagener Syndrome

Shi

Geng

et al. 2022

BioMed Research International

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Background. Primary ciliary dyskinesia (PCD) is a clinical syndrome characterized by cilia with an abnormal structure or function. Its main clinical manifestations comprise chronic bronchitis, cough, recurrent respiratory infections, situs inversus, and male infertility. Single-gene variants are widely assumed to be the main cause of this rare disease, and more than 40 genes have been described to be associated with its onset. CCDC39 is essential for assembling the inner dynein arms and dynein regulatory complex and is important in cilia motility. CCDC39 variants were reported as a monogenic etiology of PCD. Methods. This study investigated two unrelated Chinese patients diagnosed as PCD. The chest computed tomography scan was performed to identify PCD phenotypes of the two probands. Considering the effect of PCD on male fertility, routine semen analysis, sperm morphology examination, and scanning electron microscopy were performed to assess the semen characteristics of male proband in family 2 (F2 II-1), who had a history of infertility. Subsequently, the peripheral blood samples of probands were collected to perform whole-exome sequencing (WES) to explore the possible genetic causes of this disease. Results. Whole-exome sequencing revealed a homozygous CCDC39 variant in the female proband of family 1 (F1 II-1: c.286C>T:p.Arg96Ter) and two compound heterozygous CCDC39 variants in the male proband of family 2 (F2 II-1: c.732_733del: p.Ala245PhefsTer18; c.2800_2802dup:p.Val934dup). The two probands showed the typical PCD phenotypes, including chronic bronchitis, recurrent respiratory infections, and situs inversus. The male proband also showed oligoasthenoteratospermia with multiple morphological abnormalities of the sperm flagella. Additionally, CCDC39 protein level was significantly lower in the sperm of male proband than in the sperm from normal controls. Conclusion. We identified a homozygous variant reported previously and two compound heterozygous variants of CCDC39 possibly responsible for PCD pathogenesis, expanding the variant spectrum of Chinese PCD, Kartagener syndrome, and morphological abnormalities of the sperm flagella involving CCDC39.

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Ultrastructural Sperm Flagellum Defects in a Patient With CCDC39 Compound Heterozygous Mutations and Primary Ciliary Dyskinesia/Situs Viscerum Inversus

Cited by 9 publications

References 37 publications

Cryo-electron tomography of eel sperm flagella reveals a molecular “minimum system” for motile cilia

Cryo-electron tomography of eel sperm flagella reveals a molecular “minimum system” for motile cilia

Identification of DNAH17 Variants in Han-Chinese Patients With Left–Right Asymmetry Disorders

Biallelic Variants in CCDC39 Gene Lead to Primary Ciliary Dyskinesia and Kartagener Syndrome

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