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Originally published online as doi:10.2353/ajpath.2007.061002 on April 6, 2007

Published online before print April 6, 2007
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(American Journal of Pathology. 2007;170:2077-2088.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061002

Sperm Abnormalities in Heterozygous Acid Sphingomyelinase Knockout Mice Reveal a Novel Approach for the Prevention of Genetic Diseases

Avigdor Butler*, Ronald E. Gordon{dagger}, Shimon Gatt{ddagger} and Edward H. Schuchman*§

From the Departments of Human Genetics* and Pathology,{dagger} and the Institute for Gene Therapy and Molecular Medicine,§ Mount Sinai School of Medicine, New York, New York; and the Department of Biochemistry,{ddagger} Hebrew University-Hadassah School of Medicine, Jerusalem, Israel

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.






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Copyright © 2007 by the American Society for Investigative Pathology.