title: SEPT12 mutations cause male infertility with defective sperm annulus.
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.
authors.affiliation: Graduate Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yung-Che
authors.initials: YC
authors.lastname: Kuo
authors.forename: Ying-Hung
authors.initials: YH
authors.lastname: Lin
authors.forename: Hau-Inh
authors.initials: HI
authors.lastname: Chen
authors.forename: Ya-Yun
authors.initials: YY
authors.lastname: Wang
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Chiou
authors.forename: Hsi-Hui
authors.initials: HH
authors.lastname: Lin
authors.forename: Hsien-An
authors.initials: HA
authors.lastname: Pan
authors.forename: Ching-Ming
authors.initials: CM
authors.lastname: Wu
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Su
authors.forename: Chao-Chin
authors.initials: CC
authors.lastname: Hsu
authors.forename: Pao-Lin
authors.initials: PL
authors.lastname: Kuo
mesh_terms: D053627:Asthenozoospermia / Q000235:genetics; D016022:Case-Control Studies; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D058112:Septins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013081:Sperm Motility / Q000235:genetics; D013091:Spermatogenesis / Q000235:genetics; D013094:Spermatozoa / Q000002:abnormalities
chemical_list: D006160:Guanosine Triphosphate; C502729:SEPTIN12 protein, human; D058112:Septins