ClinVar

In a 33-year-old infertile male with spermatogenic failure (SPGF10; 614822), Kuo et al. (2012) identified heterozygosity for a c.589G-A transition (c.589G-A, NM_144605.3) in exon 6 of the SEPT12 gene, resulting in an asp197-to-asn (D197N) substitution at a highly conserved residue in the guanine-recognition site of the GTPase domain. The patient had oligoasthenozoospermia, with a sperm count of 0.9 x 10(6)/ml, morphology that was 80% abnormal, and a total motility of 22%. The mutation was not found in 200 fertile men with normal semen parameters. Functional analysis demonstrated that D197N mutant interfered with GTP binding and restricted filament formation of wildtype SEPT12 in a dose-dependent manner. Immunofluorescence staining showed that about 56% of the patient's abnormal sperm did not show a SEPT12 signal, compared to only about 15% of abnormal-appearing sperm from fertile men. In the patient, loss of annulus SEPT12 or SEPT4 (603696) signals were observed in sperm with abnormal morphology, indicating that SEPT12 interacts with SEPT4 to form a septin protein complex at the annulus. Some D197N sperm contained a deformed tail with reduced diameter at the midpiece-principal piece junction (annulus site).