SEPT12 mutations cause male infertility with defective sperm annulus

Yung Che Kuo, Ying Hung Lin, Hau Inh Chen, Ya Yun Wang, Yu Wei Chiou, Hsi Hui Lin, Hsien An Pan, Ching Ming Wu, Shih Ming Su, Chao Chin Hsu, Pao Lin Kuo

Research output: Contribution to journalArticlepeer-review

95 Citations (Scopus)


Septins are members of the GTPase superfamily, which has been implicated in diverse cellular functions including cytokinesis and morphogenesis. Septin 12 (SEPT12) is a testis-specific gene critical for the terminal differentiation of male germ cells. We report the identification of two missense SEPT12 mutations, c.266C>T/p.Thr89Met and c.589G>A/p.Asp197Asn, in infertile men. Both mutations are located inside the GTPase domain and may alter the protein structure as suggested by in silico modeling. The p.Thr89Met mutation significantly reduced guanosine-5′-triphosphate (GTP) hydrolytic activity, and the p.Asp197Asn mutation (SEPT12 D197N) interfered with GTP binding. Both mutant SEPT12 proteins restricted the filament formation of the wild-type SEPT12 in a dose-dependent manner. The patient carrying SEPT12 D197N presented with oligoasthenozoospermia, whereas the SEPT12 T89M patient had asthenoteratozoospermia. The characteristic sperm pathology of the SEPT12 D197N patient included defective annulus with bent tail and loss of SEPT12 from the annulus of abnormal sperm. Our finding suggests loss-of-function mutations in SEPT12 disrupted sperm structural integrity by perturbing septin filament formation.

Original languageEnglish
Pages (from-to)710-719
Number of pages10
JournalHuman Mutation
Issue number4
Publication statusPublished - Apr 1 2012
Externally publishedYes


  • Annulus
  • Filament formation
  • GTPase
  • Infertility
  • SEPT12

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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