The sperm’s ability to fertilize an egg depends on its ability to swim. The astounding motility of the sperm depends on mitochondria that power it, an acrosomal vesicle filled with enzymes that dissolve the thick walls of the egg and a protective sheath that covers it. Mutations in any of these structural components of the sperm can keep it from its destiny of reaching the egg.

Mutations that shorten, coil or remove the presence of the sperm tail of flagellum and compromise its motility are the primary causes of male infertility that affects over 20 million men worldwide.

In a new study, Na Li, PhD, and Ling Sun, PhD—research group leaders at Guangzhou Women and Children’s Medical Center, China—identified a mutation in a relatively unknown sperm protein, FSIP2 (Fibrous Sheath-Interacting Protein 2) that is a component of the sperm’s fibrous sheath in an infertile man with multiple defects in sperm flagella.

The findings are published in the article, “Hypomorphic and hypermorphic mouse models of Fsip2 indicate its dosage-dependent roles in sperm tail and acrosome formation” in the journal Development.

“The fibrous sheath covers the tails of sperm found in humans, mice and other species in which fertilization occurs within the animal’s body,” says Li. “It offers the sperm tail flexibility and strength, which is necessary for sperm to swim in the dense and sticky medium of the human body before they meet the egg. Interestingly, animals whose sperm swim through water because fertilization occurs outside of the body, such as fish, either do not have the FSIP2 protein or, at most, a defective version.”

Li, Sun, and their team of researchers generated two sets of mutant mice to study the function of FSIP2. In one of the mutant mice, they recreated the FSIP2 truncation mutation that was present in the patient. In the other mice they overexpressed the FSIP2 protein.

The researchers found that mice with the human truncated FSIP2 mutation become infertile. The semen in these mice contain fewer live sperm and over half do not swim forward, although in some the flagella still moves.

In contrast, mice that synthesize excess FSIP2 protein remain fertile and, compared to normal mice, with over seven-fold more unusually long sperm that swim faster and therefore have a better chance of fertilizing an egg.

The scientists found that the sperm of mice with the FSIP2 mutation have lower amounts of the proteins that make up the sheath covering the sperm, the mitochondrial power generators and the acrosomal vesicle.

In contrast, the sperm of the mice with excess FSIP2 make more sperm tail proteins, particularly in the fibrous sheath, which allow sperm to swim with greater ease through the body.

Through proteomic and structural analysis, the authors show changes in proteins in the fibrous sheath, mitochondrial sheath and acrosomal vesicle in FSIP2 mutants and pinpoint motifs of the protein that are evolutionarily conserved.

The discovery offers new targets for developing treatments for infertility, either by finding drugs that restore sperm movement or through correcting the debilitating mutation.