Communicated by Ming Qi
SEPT12 mutations cause male infertility with defective sperm annulus†
Article first published online: 20 FEB 2012
© 2012 Wiley Periodicals, Inc.
Special Issue: Focus on the NIH Undiagnosed Diseases Program
Volume 33, Issue 4, pages 710–719, April 2012
How to Cite
Kuo, Y.-C., Lin, Y.-H., Chen, H.-I., Wang, Y.-Y., Chiou, Y.-W., Lin, H.-H., Pan, H.-A., Wu, C.-M., Su, S.-M., Hsu, C.-C. and Kuo, P.-L. (2012), SEPT12 mutations cause male infertility with defective sperm annulus. Hum. Mutat., 33: 710–719. doi: 10.1002/humu.22028
- Issue published online: 12 MAR 2012
- Article first published online: 20 FEB 2012
- Accepted manuscript online: 20 JAN 2012 12:00AM EST
- Manuscript Accepted: 3 JAN 2012
- Manuscript Received: 15 APR 2011
- National Science Council, Taiwan. Grant Number: NSC 94-2314-B-006-075, NSC 95-2314-B-006-011, NSC 96-2314-B-006-003, NSC 97-2628-B-006-012, NSC 98-2622-B-006-004, and NSC 99-2628-B-006-027
- filament formation;
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 (SEPT12D197N) 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 SEPT12D197N presented with oligoasthenozoospermia, whereas the SEPT12T89M patient had asthenoteratozoospermia. The characteristic sperm pathology of the SEPT12D197N 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. Hum Mutat 33:710–719, 2012. © 2012 Wiley Periodicals, Inc.