Single-Nucleotide Polymorphisms in the SEPTIN12 Gene May Be a Genetic Risk Factor for Japanese Patients With Sertoli Cell-Only Syndrome

Department of Obstetrics and Gynecology, School of Medicine, Asahikawa Medical University, Asahikawa, Japan.
Journal of Andrology (Impact Factor: 2.47). 06/2011; 33(3):483-7. DOI: 10.2164/jandrol.110.012146
Source: PubMed


Genetic mechanisms have been implicated as a cause of some cases of male infertility. Recently, 10 novel genes involved in human spermatogenesis, including human SEPTIN12, were identified by expression microarray analysis of human testicular tissue. Septin12 is a member of the septin family of conserved cytoskeletal GTPases that form heteropolymeric filamentous structures in interphase cells. It is expressed specifically in the testis. Therefore, we hypothesized that mutation or polymorphisms of SEPTIN12 participate in male infertility, especially Sertoli cell-only syndrome (SCOS). To investigate whether SEPTIN12 gene defects are associated with azoospermia caused by SCOS, mutational analysis was performed in 100 Japanese patients by direct sequencing of coding regions. Statistical analysis was performed in patients with SCOS and in 140 healthy control men. No mutations were found in SEPTIN12 ; however, 8 coding single-nucleotide polymorphisms (SNP1-SNP8) could be detected in the patients with SCOS. The genotype and allele frequencies in SNP3, SNP4, and SNP6 were notably higher in the SCOS group than in the control group (P < .001). These results suggest that SEPTIN12 might play a critical role in human spermatogenesis.

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Available from: Kazuo Sengoku, Sep 29, 2014
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    • "Recently, Miyakawa et al., suggested SEPTIN12 as a good candidate gene for male infertility and chose cases with Sertoli- cell-only syndrome (SCOS) [42]. Their study enrolled 140 healthy men and 100 cases with SCOS. "
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    ABSTRACT: It is estimated that 10-15% of couples are infertile and male factors account for about half of these cases. With the advent of intracytoplasmic sperm injection (ICSI), many infertile men have been able to father offspring. However, teratozoospermia still remains a big challenge to tackle. Septins belong to a family of cytoskeletal proteins with GTPase activity and are involved in various biological processes e.g. morphogenesis, compartmentalization, apoptosis and cytokinesis. SEPTIN12, identified by c-DNA microarray analysis of infertile men, is exclusively expressed in the post meiotic male germ cells. Septin12(+/+)/Septin12(+/-) chimeric mice have multiple reproductive defects including the presence of immature sperm in the semen, and sperm with bent neck (defect of the annulus) and nuclear DNA damage. These facts make SEPTIN12 a potential sterile gene in humans. In this study, we sequenced the entire coding region of SEPTIN12 in infertile men (n = 160) and fertile controls (n = 200) and identified ten variants. Among them is the c.474 G>A variant within exon 5 that encodes part of the GTP binding domain. The variant creates a novel splice donor site that causes skipping of a portion of exon 5, resulting in a truncated protein lacking the C-terminal half of SEPTIN12. Most individuals homozygous for the c.474 A allele had teratozoospermia (abnormal sperm <14%) and their sperm showed bent tail and de-condensed nucleus with significant DNA damage. Ex vivo experiment showed truncated SEPT12 inhibits filament formation in a dose-dependent manner. This study provides the first causal link between SEPTIN12 genetic variant and male infertility with distinctive sperm pathology. Our finding also suggests vital roles of SEPT12 in sperm nuclear integrity and tail development.
    Full-text · Article · Mar 2012 · PLoS ONE
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    • "Genetic polymorphisms may also increase susceptibility to some forms of male infertility. We have identified polymorphisms of several genes that are associated with the human azoospermic population—MEI1, PRDM9 (MEISETZ), SPATA17, PARP-2, and UBR2 genes are genetic risk factors for the patients with azoospermia by meiotic arrest [48–52], and polymorphisms of the SEPTIN12 gene are associated with patients with Sertoli cell-only syndrome [53]. Genetic polymorphisms and male infertility have been under much investigation recently. "
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    ABSTRACT: Infertility is one of the most serious social problems facing advanced nations. In general, approximate half of all cases of infertility are caused by factors related to the male partner. To date, various treatments have been developed for male infertility and are steadily producing results. However, there is no effective treatment for patients with nonobstructive azoospermia, in which there is an absence of mature sperm in the testes. Although evidence suggests that many patients with male infertility have a genetic predisposition to the condition, the cause has not been elucidated in the vast majority of cases. This paper discusses the environmental factors considered likely to be involved in male infertility and the genes that have been clearly shown to be involved in male infertility in humans, including our recent findings.
    Full-text · Article · Jan 2012 · Advances in Urology
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    ABSTRACT: SEPTINS (FULL NAME: Septin; symbol name: SEPT) belong to a family of polymerizing GTP-binding proteins that are required for many cellular functions, including membrane compartmentalization, vesicle trafficking, mitosis and cytoskeletal remodeling. Two of the 14 family members in the mammalian species, Septin12 and 14 are expressed specifically in the testis. In the mouse, knockout of Septin4 and Septin12 leads to male sterility with distinctive sperm pathology (defective annulus or bent neck). In humans, sperm with abnormal expression patterns of SEPT4, 7 and 12 are more prevalent in infertile men. How septin filament is assembled/dissembled and how the SEPT-related complex regulates spermatogenesis still await further investigation.
    Full-text · Article · Oct 2011
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