SEPTIN12 Genetic Variants Confer Susceptibility to Teratozoospermia

Lin, Ying; Wang, Ya Yun; Chen, Hau Inh; Kuo, Yung Che; Chiou, Yu Wei; Lin, Hsi Hui; Wu, Ching Ming; Hsu, Chao Chin; Chiang, Han Sun; Kuo, Pao Lin

doi:10.1371/journal.pone.0034011

Cited by 41 publications

(43 citation statements)

References 76 publications

(120 reference statements)

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“…In addition; YingHung Lin et al had found two missense mutations in men with infertility compared with controls located in the predicted GTP-binding domain of septin 12 [15]. Also, Kuo et al, reported a patient with a variation in SEPT12 (D197N) which had sperm with defective annulus with bent tail and loss of septin 12 from the annulus of abnormal sperm [16].…”

Section: Discussionmentioning

confidence: 99%

Relationship between absence of annulus and asthenozoospermia in Iranian men

Hosseinifar

Shafipour

Modarresi

et al. 2014

J Assist Reprod Genet

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Purpose To find a relationship between absence of annulus and asthenozoospermia in Iranian men. Methods In the present study, semen samples from 100 asthenozoospermic and 20 normozospermic patients were analyzed for sperm concentration and motility. Spermatozoa were immunostained for the two septin subunits Sept4 and Sept7. The absence of the annulus structure was confirmed by transmission electron microscopy and western blot analysis for septin 4. DNA sequencing for all coding exons of SEPT12 was performed for a patient using peripheral blood sample. Results Specific antibodies for SEPT4 and SEPT7 consistently labeled the annuli in spermatozoa from all of the 20 normozospermic men, while in one of 100 patients with asthenozoospermia, 75 % of sperms lacking septin 4 or septin 7 proteins at the annulus. It was shown that the structural defect in annulus formation is not caused by point mutation of SEPT12 gene. ConclusionsIn conclusion, the results of this study demonstrated that the frequency of the absence of annulus in asthenozoospermic sample of Iranian population has a low frequency and could not be assume as a diagnostic marker for classifying asthenozoospermic patients.

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Section: Discussionmentioning

confidence: 99%

Relationship between absence of annulus and asthenozoospermia in Iranian men

Hosseinifar

Shafipour

Modarresi

et al. 2014

J Assist Reprod Genet

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“…) and one sequence variant (c.474G.A) have been identified in infertile men with distinctive sperm pathology, such as a defective annulus with a bent tail Lin et al, 2012). The two missense mutations are located within the GTP-binding domain of SEPT12.…”

Section: D197nmentioning

confidence: 99%

SEPT12 orchestrates the formation of mammalian sperm annulus by organizing SEPT12-7-6-2/-4 core complexes

Kuo

Shen

Chen

et al. 2015

Journal of Cell Science

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BSTRACTMale infertility has become a worldwide health problem, but the etiologies of most cases are still unknown. SEPT12, a GTP-binding protein, is involved in male fertility. Two SEPT12 mutations (SEPT12 T89M and SEPT12 D197N ) have been identified in infertile men who have a defective sperm annulus with a bent tail. The function of SEPT12 in the sperm annulus is still unclear. Here, we found that SEPT12 formed a filamentous structure with SEPT7, SEPT 6, SEPT2 and SEPT4 at the sperm annulus. The SEPT12-based septin core complex was assembled as octameric filaments comprising the SEPT proteins 12-7-6-2-2-6-7-12 or 12-7-6-4-4-6-7-12. In addition, the GTP-binding domain of SEPT12 was crucial for its interaction with SEPT7, and the N-and C-termini of SEPT12 were required for the interaction of SEPT12 with itself to polymerize octamers into filaments. Mutant mice carrying the SEPT12 D197N mutation, which disrupts SEPT12 filament formation, showed a disorganized sperm annulus, bent tail, reduced motility and loss of the SEPT ring structure at the sperm annulus. These phenotypes were also observed in an infertile man carrying SEPT12 D197N .Taken together, our results demonstrate the molecular architecture of SEPT12 filaments at the sperm annulus, their mechanical support of sperm motility, and their correlation with male infertility.

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“…In our previous study, SEPT12 mutations in human and mice spermatozoa were demonstrated to cause teratozoospermia (e.g., nuclear damage, premature chromosomal condensation, and abnormal morphologies of sperm heads and tails) [13,14,15,25]. NDC1 was identified as a SEPT12 interactor through the yeast 2-hybrid system by using a human testicular cDNA library [17].…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, sperm from SEPT12-mutated mice exhibited unique morphological defects (e.g., immature sperm head, bent tail, premature chromosomal condensation, and nuclear damage) [13]. In humans, SEPT12 mutations in infertile men result in teratozoospermia and oligozoospermia [14,15,16]. In addition, several nuclear or nuclear membrane-related proteins were identified as SEPT12 interactors through the yeast 2-hybrid system; one of these interactors is NDC1 [17].…”

Section: Introductionmentioning

confidence: 99%

SEPT12–NDC1 Complexes Are Required for Mammalian Spermiogenesis

Lai

Wang

et al. 2016

IJMS

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Male factor infertility accounts for approximately 50 percent of infertile couples. The male factor-related causes of intracytoplasmic sperm injection failure include the absence of sperm, immotile sperm, immature sperm, abnormally structured sperm, and sperm with nuclear damage. Our knockout and knock-in mice models demonstrated that SEPTIN12 (SEPT12) is vital for the formation of sperm morphological characteristics during spermiogenesis. In the clinical aspect, mutated SEPT12 in men results in oligozoospermia or teratozoospermia or both. Sperm with mutated SEPT12 revealed abnormal head and tail structures, decreased chromosomal condensation, and nuclear damage. Furthermore, several nuclear or nuclear membrane-related proteins have been identified as SEPT12 interactors through the yeast 2-hybrid system, including NDC1 transmembrane nucleoporin (NDC1). NDC1 is a major nuclear pore protein, and is critical for nuclear pore complex assembly and nuclear morphology maintenance in mammalian cells. Mutated NDC1 cause gametogenesis defects and skeletal malformations in mice, which were detected spontaneously in the A/J strain. In this study, we characterized the functional effects of SEPT12–NDC1 complexes during mammalian spermiogenesis. In mature human spermatozoa, SEPT12 and NDC1 are majorly colocalized in the centrosome regions; however, NDC1 is only slightly co-expressed with SEPT12 at the annulus of the sperm tail. In addition, SEPT12 interacts with NDC1 in the male germ cell line through coimmunoprecipitation. During murine spermiogenesis, we observed that NDC1 was located at the nuclear membrane of spermatids and at the necks of mature spermatozoa. In male germ cell lines, NDC1 overexpression restricted the localization of SEPT12 to the nucleus and repressed the filament formation of SEPT12. In mice sperm with mutated SEPT12, NDC1 dispersed around the manchette region of the sperm head and annulus, compared with concentrating at the sperm neck of wild-type sperm. These results indicate that SEPT12–NDC1 complexes are involved in mammalian spermiogenesis.

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SEPTIN12 Genetic Variants Confer Susceptibility to Teratozoospermia

Cited by 41 publications

References 76 publications

Relationship between absence of annulus and asthenozoospermia in Iranian men

Relationship between absence of annulus and asthenozoospermia in Iranian men

SEPT12 orchestrates the formation of mammalian sperm annulus by organizing SEPT12-7-6-2/-4 core complexes

SEPT12–NDC1 Complexes Are Required for Mammalian Spermiogenesis

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