• PMID: 22479503
• Gene Name: SEPTIN12
• Condition: Teratozoospermia, male infertility
• Association: This study provides the first causal link between SEPTIN12 genetic variant and male infertility with distinctive sperm pathology. The study finding also suggests vital roles of SEPT12 in sperm nuclear integrity and tail development.
• Mutation: c.474 G>A
• Population size: 360
• Population details: 360 (160 infertile men, 200 fertile controls)
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Teratozoospermia, male infertility

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.

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. FAU - Lin, Ying-Hung AU - Lin YH AD - Graduate Institute of Basic Medicine, Fu Jen Catholic University, College of Medicine, Taipei, Taiwan. FAU - Wang, Ya-Yun AU - Wang YY FAU - Chen, Hau-Inh AU - Chen HI FAU - Kuo, Yung-Che AU - Kuo YC FAU - Chiou, Yu-Wei AU - Chiou YW FAU - Lin, Hsi-Hui AU - Lin HH FAU - Wu, Ching-Ming AU - Wu CM FAU - Hsu, Chao-Chin AU - Hsu CC FAU - Chiang, Han-Sun AU - Chiang HS