Premium
SEPT12 mutations cause male infertility with defective sperm annulus
Author(s) -
Kuo YungChe,
Lin YingHung,
Chen HauInh,
Wang YaYun,
Chiou YuWei,
Lin HsiHui,
Pan HsienAn,
Wu ChingMing,
Su ShihMing,
Hsu ChaoChin,
Kuo PaoLin
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22028
Subject(s) - septin , biology , missense mutation , gtpase , mutant , microbiology and biotechnology , mutation , cytokinesis , sperm , genetics , gene , cell , cell division
Abstract 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. Hum Mutat 33:710–719, 2012. © 2012 Wiley Periodicals, Inc.