A Heterozygous Mutation Disrupting the SPAG16 Gene Results in Biochemical Instability of Central Apparatus Components of the Human Sperm Axoneme1

Zhang, Zhibing; Zariwala, Maimoona A.; Mahadevan, Maha M.; Caballero-Campo, Pedro; Shen, Xue‐Ning; Escudier, Estelle; Duriez, Bénédicte; Bridoux, Anne Marie; Leigh, Margaret W.; Gerton, George L.; Kennedy, Marcus P.; Amselem, Serge; Knowles, Michael R.; Strauss, Jerome F.

doi:10.1095/biolreprod.107.063206

Cited by 41 publications

(51 citation statements)

References 33 publications

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“…Although the Spag17 mutants developed a phenotype consistent with PCD, we did not find situs inversus in the Spag17 2/2 mice, which is in accordance with findings in other CP protein knockout murine models (11)(12)(13)(14). Moreover, no cardiac structural defects were observed in nullizygous mice ( Figure E1A in the online supplement).…”

Section: The Phenotype Of Spag17-deficient Micesupporting

confidence: 91%

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Sperm-Associated Antigen–17 Gene Is Essential for Motile Cilia Function and Neonatal Survival

Teves¹,

Zhang²,

Costanzo³

et al. 2013

Am J Respir Cell Mol Biol

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Primary ciliary dyskinesia (PCD), resulting from defects in cilia assembly or motility, is caused by mutations in a number of genes encoding axonemal proteins. PCD phenotypes are variable, and include recurrent respiratory tract infections, bronchiectasis, hydrocephaly, situs inversus, and male infertility. We generated knockout mice for the sperm-associated antigen-17 (Spag17) gene, which encodes a central pair (CP) protein present in the axonemes of cells with "9 1 2" motile cilia or flagella. The targeting of Spag17 resulted in a severe phenotype characterized by immotile nasal and tracheal cilia, reduced clearance of nasal mucus, profound respiratory distress associated with lung fluid accumulation and disruption of the alveolar epithelium, cerebral ventricular expansion consistent with emerging hydrocephalus, failure to suckle, and neonatal demise within 12 hours of birth. Ultrastructural analysis revealed the loss of one CP microtubule in approximately one quarter of tracheal cilia axonemes, an absence of a C1 microtubule projection, and other less frequent CP structural abnormalities. SPAG6 and SPAG16 (CP proteins that interact with SPAG17) were increased in tracheal tissue from SPAG17-deficient mice. We conclude that Spag17 plays a critical role in the function and structure of motile cilia, and that neonatal lethality is likely explained by impaired airway mucociliary clearance.Keywords: primary ciliary dyskinesia; axoneme; central pair; Spag17; cilia Cilia are organelles that play key roles, including the determination of left-right asymmetry in the body; clearing mucus, particles, and fluid out of the airways; and facilitating the flow of cerebrospinal fluid (CSF) (1). Primary ciliary dyskinesia (PCD), which results from defects in the formation and function of cilia and flagella, is a relatively rare disorder affecting 1 in 16,000 individuals worldwide (2). The axoneme, the highly conserved cytoskeletal structure of motile cilia, has a "9 1 2" arrangement consisting of nine outer doublet microtubules surrounding a central microtubule pair. Motility is dependent upon proteins associated with the outer doublet microtubules, including dynein arms, radial spokes, and nexin links.The sliding of the outer doublet microtubules is modulated by the central pair (CP) apparatus (2-4). The two microtubules in the CP are structurally and biochemically dimorphic, and by convention receive separate designations (e.g., C1 and C2). At least 10 different polypeptides are uniquely associated with the C1 microtubule, and seven are unique to the C2 microtubule (3-6). This biochemical and structural asymmetry is believed to have functional significance with respect to the cilia or flagellar beat and waveform (7).The mammalian sperm-associated antigen-17 protein (SPAG17) is the orthologue of Chlamydomonas reinhardtii PF6 (8), a protein located on a projection from the C1 CP microtubule in green algae (9). The PF6 protein interacts with a number of other proteins, including calmodulin, and ultimately influences the radial s...

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Section: The Phenotype Of Spag17-deficient Micesupporting

confidence: 91%

“…Chlamydomonas pf6 mutants demonstrate paralyzed flagella, and lack the CP 1a projection (9). The full-length murine SPAG17 protein is 250 kD, like its Chlamydomonas orthologue, and it is found in testes and tissues with motile cilia (8,11). The present study sought to determine whether mammalian SPAG17 plays an essential role in mammalian motile cilia.…”

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confidence: 99%

Sperm-Associated Antigen–17 Gene Is Essential for Motile Cilia Function and Neonatal Survival

Teves¹,

Zhang²,

Costanzo³

et al. 2013

Am J Respir Cell Mol Biol

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“…In addition, cauda spermatozoa from Pla2g3 -/-mice had aberrant flagellar structures with unusual outer and inner dynein arms, a central pair of microtubules, and a fibrous sheath ( Figure 5). In fact, spermatozoa from mice harboring abnormal flagella, due to defects in flagellar axoneme proteins such as Spag6, Spag16, Tekt2, Pacrg, and Akap4, are commonly unable to swim and fail to reach the oviducts in females (49)(50)(51)(52)(53), events that are reminiscent of Pla2g3 -/-mice. Interestingly, flagellar abnormality in Pla2g3 -/-spermatozoa was less obvious in the testis and caput epididymidis than in the cauda epididymidis ( Figure 5, E and F), suggesting that the observed structural changes in Pla2g3 -/-spermatozoa mainly take place during epididymal transit from the caput to cauda epididymidis.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, some Pla2g3 -/-sperm had developed double axonemes in the principal piece and even in the midpiece of the flagellum, where outer dense fibers were mislocated outside the mitochondrial lines ( Figure 5B). Such alterations have often been observed in mutant mice harboring (even haploinsufficient) defects in structural proteins for flagellar axonemes (49)(50)(51)(52)(53). In addition, the acrosomes of some spermatozoa from Pla2g3 -/-mice were unusually expanded ( Figure 5C), and vacuoles were often found beneath the acrosome cap ( Figure 5C).…”

Section: Figurementioning

confidence: 91%

Group III secreted phospholipase A2 regulates epididymal sperm maturation and fertility in mice

Sato¹,

Taketomi²,

Isogai³

et al. 2010

J. Clin. Invest.

107

106

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Although lipid metabolism is thought to be important for the proper maturation and function of spermatozoa, the molecular mechanisms that underlie this dynamic process in the gonads remains incompletely understood. Here, we show that group III phospholipase A 2 (sPLA 2 -III), a member of the secreted phospholipase A 2 (sPLA 2 ) family, is expressed in the mouse proximal epididymal epithelium and that targeted disruption of the gene encoding this protein (Pla2g3) leads to defects in sperm maturation and fertility. Although testicular spermatogenesis in Pla2g3 -/-mice was grossly normal, spermatozoa isolated from the cauda epididymidis displayed hypomotility, and their ability to fertilize intact eggs was markedly impaired. Transmission EM further revealed that epididymal spermatozoa in Pla2g3 -/-mice had both flagella with abnormal axonemes and aberrant acrosomal structures. During epididymal transit, phosphatidylcholine in the membrane of Pla2g3 +/+ sperm underwent a dramatic shift in its acyl groups from oleic, linoleic, and arachidonic acids to docosapentaenoic and docosahexaenoic acids, whereas this membrane lipid remodeling event was compromised in sperm from Pla2g3 -/-mice. Moreover, the gonads of Pla2g3 -/-mice contained less 12/15-lipoxygenase metabolites than did those of Pla2g3 +/+ mice. Together, our results reveal a role for the atypical sPLA 2 family member sPLA 2 -III in epididymal lipid homeostasis and indicate that its perturbation may lead to sperm dysfunction.

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“…Ce phénotype est souvent retrouvé chez les sujets d'une même fratrie et dans des cas de consanguinité, ce qui indique une origine génétique mais aucun gène n'a été identifié à ce jour. L'absence de doublets axonémaux 1, 2 et 9 associée à une absence partielle des microtubules centraux est d'origine génétique, comme le suggère la présence d'une mutation à l'état hétérozygote du gène SPAG16 (sperm associated antigen 16) chez deux frères et l'observation des mêmes anomalies chez les souris Spag16 -/- [33]. Un seul gène impliqué dans une anomalie d'une structure non axonémale est connu chez l'homme.…”

Section: Origine Génétique Des Malformations Du Flagelle Du Spermatozunclassified

Malformations de l’appareil flagellaire du spermatozoïde impliquées dans l’infertilité chez l’homme

Escalier

Touré

2012

Med Sci (Paris)

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> La morphogenèse du flagelle du spermatozoïde humain fait intervenir des processus et des composants cellulaires spécifiques. Des malformations des différentes structures internes du flagelle (axonème et structures périaxonémales) sont associées à une infertilité. Ces malformations peuvent être classées en 15 phénotypes principaux dont la majorité sont associées à une consanguinité et/ou une incidence familiale, suggérant une origine génétique, bien qu'à ce jour très peu de gènes aient été formellement impliqués. < Structure et mise en place du flagelle chez l'hommeLa formation du flagelle du spermatozoïde fait intervenir des processus morphogénétiques complexes et spécifiques de la spermiogenèse, dont les mécanismes moléculaires restent pour la plupart non éluci-dés. Ces processus, ainsi que plusieurs anomalies morphologiques du spermatozoïde humain, ont été particulièrement bien décrits, sur la base d'observations en microscopique électronique, dans deux atlas de référence [3,4] ; ils sont schématisés dans la Figure 1A. Le flagelle du spermatozoïde peut être décomposé en quatre principaux segments : la pièce connective, la pièce intermédiaire, la pièce principale et la pièce terminale (Figure 1B). La pièce connective, région la plus proximale du flagelle, est ancrée sur le noyau et renferme les deux centrioles. Le centriole distal se prolonge par l'axonème, lui-même associé à des fibres denses de longueurs inégales (Figures 2A, 2B). La région juxtaproximale, appelée pièce intermé-diaire, est composée de mitochondries disposées en hélice autour des fibres denses et de l'axonème. La pièce intermédiaire est connectée à la pièce principale par l'annulus, aussi appelé anneau de Jensen. La pièce principale comprend les structures axiales du flagelle : elles ne sont pas recouvertes de mitochondries (axonème associé ou non à des fibres denses) mais sont entourées par la gaine fibreuse. Finalement, la pièce terminale, région la plus distale du flagelle, ne comprend que l'axonème (Figure 2A). L'ensemble de ces structures flagellaires, interconnectées les unes avec les autres, est recouvert par la membrane plasmique. C'est cette cohésion structurale qui assure le maintien de

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A Heterozygous Mutation Disrupting the SPAG16 Gene Results in Biochemical Instability of Central Apparatus Components of the Human Sperm Axoneme1

Cited by 41 publications

References 33 publications

Sperm-Associated Antigen–17 Gene Is Essential for Motile Cilia Function and Neonatal Survival

Sperm-Associated Antigen–17 Gene Is Essential for Motile Cilia Function and Neonatal Survival

Group III secreted phospholipase A2 regulates epididymal sperm maturation and fertility in mice

Malformations de l’appareil flagellaire du spermatozoïde impliquées dans l’infertilité chez l’homme

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