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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

Identification of novel variants in the SEPTIN12 gene.Genomic structure of the SEPTIN12 gene and positions of the ten SNPs. Open bars indicate exons. The ATG start site is located at exon 2. Exon 3 to exon 8 encodes the GTP -Binding Domain of SETIN12. (B.–C.) Electropherograms showing DNA sequences. Lower panels show the variant (c.474C→A, Left; c.494T→A, Right) sequences, whereas the upper panels show the wild-type (normal) sequences. Red stars indicate locations of the variants.
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pone-0034011-g001: Identification of novel variants in the SEPTIN12 gene.Genomic structure of the SEPTIN12 gene and positions of the ten SNPs. Open bars indicate exons. The ATG start site is located at exon 2. Exon 3 to exon 8 encodes the GTP -Binding Domain of SETIN12. (B.–C.) Electropherograms showing DNA sequences. Lower panels show the variant (c.474C→A, Left; c.494T→A, Right) sequences, whereas the upper panels show the wild-type (normal) sequences. Red stars indicate locations of the variants.

Mentions: A total of 160 infertile men with abnormal semen parameters and 200 fertile controls were subjected to SEPTIN12 sequence analysis. Ten SNPs identified included seven intronic variants (IVS1+83A>G, IVS1+316A>G, IVS1+334C>T, c.375−1G>A, IVS5+71A>G, IVS6+35G>A and IVS8+7G>A), one synonymous variant (c.474G>A) and two non-synonymous variant (c.332C>A, pThr111Lys; c.494T>A, p.Val165Gln). Their locations are shown in Figure 1A. Six SNPs are located between exon 3 to exon 8, which encode the GTP binding domain critical for the polymerization of SEPT. They are c.332C>A, c.375−1G>A, c.474G>A, c.494T>A, IVS5+71A>G and IVS6+35G>A (Figure 1A). Both allele and genotype frequencies of c.474 A were more prevalent in the infertile men (p  = 0.007 and 0.003, respectively) (Figure 1B and Table 1). Another SNP, c.494T>A SNP, was more prevalent in the control subjects (p = 0.032 and 0.013, respectively) (Figure 1B and Table 1).


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)

Identification of novel variants in the SEPTIN12 gene.Genomic structure of the SEPTIN12 gene and positions of the ten SNPs. Open bars indicate exons. The ATG start site is located at exon 2. Exon 3 to exon 8 encodes the GTP -Binding Domain of SETIN12. (B.–C.) Electropherograms showing DNA sequences. Lower panels show the variant (c.474C→A, Left; c.494T→A, Right) sequences, whereas the upper panels show the wild-type (normal) sequences. Red stars indicate locations of the variants.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0034011-g001: Identification of novel variants in the SEPTIN12 gene.Genomic structure of the SEPTIN12 gene and positions of the ten SNPs. Open bars indicate exons. The ATG start site is located at exon 2. Exon 3 to exon 8 encodes the GTP -Binding Domain of SETIN12. (B.–C.) Electropherograms showing DNA sequences. Lower panels show the variant (c.474C→A, Left; c.494T→A, Right) sequences, whereas the upper panels show the wild-type (normal) sequences. Red stars indicate locations of the variants.
Mentions: A total of 160 infertile men with abnormal semen parameters and 200 fertile controls were subjected to SEPTIN12 sequence analysis. Ten SNPs identified included seven intronic variants (IVS1+83A>G, IVS1+316A>G, IVS1+334C>T, c.375−1G>A, IVS5+71A>G, IVS6+35G>A and IVS8+7G>A), one synonymous variant (c.474G>A) and two non-synonymous variant (c.332C>A, pThr111Lys; c.494T>A, p.Val165Gln). Their locations are shown in Figure 1A. Six SNPs are located between exon 3 to exon 8, which encode the GTP binding domain critical for the polymerization of SEPT. They are c.332C>A, c.375−1G>A, c.474G>A, c.494T>A, IVS5+71A>G and IVS6+35G>A (Figure 1A). Both allele and genotype frequencies of c.474 A were more prevalent in the infertile men (p  = 0.007 and 0.003, respectively) (Figure 1B and Table 1). Another SNP, c.494T>A SNP, was more prevalent in the control subjects (p = 0.032 and 0.013, respectively) (Figure 1B and Table 1).

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