Sperm abnormalities in heterozygous acid sphingomyelinase knockout mice reveal a novel approach for the prevention of genetic diseases.

ABSTRACT

Acid sphingomyelinase knockout mice are a model of the inherited human disorder types A and B Niemann-Pick disease. Herein, we show that heterozygous (ASMKO(+/-)) mice have two distinct sperm populations resembling those found in normal and mutant animals, respectively, and that these two populations could be distinguished by their morphology, ability to undergo capacitation or the acrosome reaction, and/or mitochondrial membrane potential (MMP). The abnormal morphology of the mutant sperm could be normalized by demembranation with detergents or by the addition of recombinant acid sphingomyelinase to the culture media, and the corrected sperm also had an enhanced fertilization capacity. Methods were then explored to enrich for normal sperm from the mixed ASMKO(+/-) population, and flow cytometric sorting based on MMP provided the best results. In vitro fertilization was performed using ASMKO(+/-) oocytes and sperm before and after MMP sorting, and it was found that the sorted sperm produced significantly more wild-type pups than nonsorted sperm. Sperm sorting is much less invasive and more cost-effective than egg isolation, and offers several advantages over the existing assisted reproduction options for Niemann-Pick disease carrier couples. It therefore could have a major impact on the prevention of this and perhaps other genetic diseases.