Molecular defects responsible for morphologically abnormal spermatozoa (teratospermia) associated with male sterility are largely unknown. We report defective expression of protein 4.1, a cytoskeletal protein initially recognised in red cells. In some patients with severely amorphous sperm heads, protein 4.1 had an abnormal sub-cellular localisation (tail instead of head) and appeared as high-molecular-weight isoforms, especially a 135 kDa species instead of the 82 kDa isoform seen in fertile sperm. Because the 135 kDa isoform is characteristic of immature germ cells from testis, its presence in teratospermia suggests profoundly disturbed sperm differentiation.
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