Nature Genetics
28, 82 - 86 (2001)
doi:10.1038/ng0501-82
Haploinsufficiency of protamine-1 or -2 causes infertility in miceChunghee Cho1, 2, 4, William D. Willis1, 4, Eugenia H. Goulding1, Haesook Jung-Ha1, Young-Chul Choi3, Norman B. Hecht3
& Edward M. Eddy11
Gamete Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA. 2
Present address: Department of Life Sciences, Kwangji Institute of Science and Technology (K-JIST), Kwangji, Republic of Korea. 3
Center for Research on Reproduction and Women's Health and Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Edward M. Eddy eddy@niehs.nih.govProtamines are the major DNA-binding proteins in the nucleus of sperm in most vertebrates1,
2,
3,
4,
5 and package the DNA in a volume less than 5% of a somatic cell nucleus6. Many mammals have one protamine, but a few species, including humans and mice, have two7,
8,
9,
10,
11,
12,
13. Here we use gene targeting to determine if the second protamine provides redundancy to an essential process, or if both protamines are necessary. We disrupted the coding sequence of one allele of either Prm1 or Prm2 in embryonic stem (ES) cells derived from 129-strain mice, and injected them into blastocysts from C57BL/6-strain mice. Male chimeras produced 129-genotype sperm with disrupted Prm1 or Prm2 alleles, but failed to sire offspring carrying the 129 genome. We also found that a decrease in the amount of either protamine disrupts nuclear formation, processing of protamine-2 and normal sperm function. Our studies show that both protamines are essential and that haploinsufficiency caused by a mutation in one allele of Prm1 or Prm2 prevents genetic transmission of both mutant and wild-type alleles.
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