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Sms1 and its role in male infertility

H&E staining of Sms1-/- with accumulation of round cells (black arrow heads) in the epididymal lumen.

Sphingolipids are essential components of cellular membranes and are required for lipid raft formation. Sphingomyelin synthase 1 (SMS1/SGMS1) and the isoenzyme SMS2 both catalyze the de novo synthesis of sphingomyelin (SM) and diacylglycerol (DAG) from ceramide (Cer) and phosphatidylcholine (PC).

SM and other complex sphingolipids (SL) have various functions in structure, adhesion and signaling. Loss of function mutations of various catabolic enzymes of the sphingolipid pathway can lead to lipid storage diseases such as Niemann-Pick, Gaucher's, Tay-Sachs and others.

Scientists around Thomas Floss and Tobias Hartmann analyzed the role of SMS1 in testis. During sperm maturation, the sphingolipid metabolism is an essential process. Several mutations in enzymes of the SL metabolism caused severely impaired fertility. The scientists created an insertional mutation in the gene for the anabolic enzyme SMS1 and studied its consequences for male fertility.

Among several investigations, RNA expression profiling as well as pathology was performed in the German Mouse Clinic. Taken together, the result of the different analyses showed that infertility was observed in 66% of Sms1 homozygous mutant adult males. Infertility was caused by sloughing of meiotic and spermatid stages with subsequent accumulation in the epididymides. In addition, the injection of fluorescent dyes demonstrated a defective Blood-Testis Barrier (BTB). Lipid profiling of testes revealed a decrease of LC-PUFAs in Sms1-/- animals. Male infertility was ameliorated by supplementary diet of DHA and EPA ('fish oil'), indicating an essential role for SMS1 in the supply with n-3 unsaturated long-chain FA substrates for the formation of the BTB and the syncytium.

Wittmann A, Grimm MO, Scherthan H, Horsch M, Beckers J, Fuchs H, Gailus-Durner V, Hrabě de Angelis M, Ford SJ, Burton NC, Razansky D, Trümbach D, Aichler M, Walch AK, Calzada-Wack J, Neff F, Wurst W, Hartmann T, Floss T. Sphingomyelin Synthase 1 Is Essential for Male Fertility in Mice. PLoS One. 2016 Oct 27;11(10):e0164298. doi: 10.1371/journal.pone.0164298. eCollection 2016.