SEPTIN12 genetic variants confer susceptibility to teratozoospermia

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

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Article numbere34011
JournalPLoS ONE
Volume7
Issue number3
DOIs
Publication statusPublished - Mar 30 2012
Externally publishedYes

Fingerprint

Spermatozoa
spermatozoa
Exons
DNA
Septins
Defects
RNA Splice Sites
Cytoskeletal Proteins
GTP Phosphohydrolases
Pathology
Microarrays
Guanosine Triphosphate
DNA damage
DNA Damage
exons
Tail
tail
Genes
Cells
Apoptosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Lin, Y. H., Wang, Y. Y., Chen, H. I., Kuo, Y. C., Chiou, Y. W., Lin, H. H., ... Kuo, P. L. (2012). SEPTIN12 genetic variants confer susceptibility to teratozoospermia. PLoS ONE, 7(3), [e34011]. https://doi.org/10.1371/journal.pone.0034011

SEPTIN12 genetic variants confer susceptibility to teratozoospermia. / Lin, Ying Hung; 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.

In: PLoS ONE, Vol. 7, No. 3, e34011, 30.03.2012.

Research output: Contribution to journalArticle

Lin, YH, Wang, YY, Chen, HI, Kuo, YC, Chiou, YW, Lin, HH, Wu, CM, Hsu, CC, Chiang, HS & Kuo, PL 2012, 'SEPTIN12 genetic variants confer susceptibility to teratozoospermia', PLoS ONE, vol. 7, no. 3, e34011. https://doi.org/10.1371/journal.pone.0034011
Lin, Ying Hung ; 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. / SEPTIN12 genetic variants confer susceptibility to teratozoospermia. In: PLoS ONE. 2012 ; Vol. 7, No. 3.
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AU - Lin, Hsi Hui

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