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SEPTIN12 genetic variants confer susceptibility to teratozoospermia.

Lin YH, Wang YY, Chen HI, Kuo YC, Chiou YW, Lin HH, Wu CM, Hsu CC, Chiang HS, Kuo PL - PLoS ONE (2012)

Bottom Line: 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.Our finding also suggests vital roles of SEPT12 in sperm nuclear integrity and tail development.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Basic Medicine, Fu Jen Catholic University, College of Medicine, Taipei, Taiwan.

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.

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Related in: MedlinePlus

Abnormal morphology of spermatozoa from a case with c.474A/A.(A.) Motile sperm organelle morphology examination (MSOME) for sperm cells using a high-magnification inverted microscope (magnification was ×8400). (a.) sperm from a fertile control with c.474C/C; (b.–d.) sperm from an infertile man with c.474A/A. Sperm with bent-tail (b.), neck(c.) and round head (d.). (B.) IFA assay for sperm from a fertile control with c.474C/C (a.) and an infertile man with c.474A/A (b.). DAPI: blue; mito-tracker: red. (Magnification: ×400).
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pone-0034011-g002: Abnormal morphology of spermatozoa from a case with c.474A/A.(A.) Motile sperm organelle morphology examination (MSOME) for sperm cells using a high-magnification inverted microscope (magnification was ×8400). (a.) sperm from a fertile control with c.474C/C; (b.–d.) sperm from an infertile man with c.474A/A. Sperm with bent-tail (b.), neck(c.) and round head (d.). (B.) IFA assay for sperm from a fertile control with c.474C/C (a.) and an infertile man with c.474A/A (b.). DAPI: blue; mito-tracker: red. (Magnification: ×400).

Mentions: In this study, 9 of the 15 infertile men with c.474A/A were presented with teratozoospermia (88%–99% of abnormal sperm) (Table 2). To detail the morphological pattern of their spermatozoa, motile sperm organelle morphology examination (MSOME) and immuno-fluorescence assay (IFA) were performed. Most sperm were found to have distinct pathological features, including bent-tail, head with abnormal shape and immature spermatid (Figure 2A and 2B).


SEPTIN12 genetic variants confer susceptibility to teratozoospermia.

Lin YH, Wang YY, Chen HI, Kuo YC, Chiou YW, Lin HH, Wu CM, Hsu CC, Chiang HS, Kuo PL - PLoS ONE (2012)

Abnormal morphology of spermatozoa from a case with c.474A/A.(A.) Motile sperm organelle morphology examination (MSOME) for sperm cells using a high-magnification inverted microscope (magnification was ×8400). (a.) sperm from a fertile control with c.474C/C; (b.–d.) sperm from an infertile man with c.474A/A. Sperm with bent-tail (b.), neck(c.) and round head (d.). (B.) IFA assay for sperm from a fertile control with c.474C/C (a.) and an infertile man with c.474A/A (b.). DAPI: blue; mito-tracker: red. (Magnification: ×400).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3316533&req=5

pone-0034011-g002: Abnormal morphology of spermatozoa from a case with c.474A/A.(A.) Motile sperm organelle morphology examination (MSOME) for sperm cells using a high-magnification inverted microscope (magnification was ×8400). (a.) sperm from a fertile control with c.474C/C; (b.–d.) sperm from an infertile man with c.474A/A. Sperm with bent-tail (b.), neck(c.) and round head (d.). (B.) IFA assay for sperm from a fertile control with c.474C/C (a.) and an infertile man with c.474A/A (b.). DAPI: blue; mito-tracker: red. (Magnification: ×400).
Mentions: In this study, 9 of the 15 infertile men with c.474A/A were presented with teratozoospermia (88%–99% of abnormal sperm) (Table 2). To detail the morphological pattern of their spermatozoa, motile sperm organelle morphology examination (MSOME) and immuno-fluorescence assay (IFA) were performed. Most sperm were found to have distinct pathological features, including bent-tail, head with abnormal shape and immature spermatid (Figure 2A and 2B).

Bottom Line: 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.Our finding also suggests vital roles of SEPT12 in sperm nuclear integrity and tail development.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Basic Medicine, Fu Jen Catholic University, College of Medicine, Taipei, Taiwan.

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.

Show MeSH
Related in: MedlinePlus