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Gene Review

PRM1  -  protamine 1

Homo sapiens

Synonyms: CT94.1, Cysteine-rich protamine, P1, Sperm protamine P1
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Disease relevance of PRM1

  • Sperm protamine deficiency has been associated with human male infertility [1].
  • Changes in the expression of P1 and P2 protamines have been found to be associated with infertility in man [2].
  • For this reason, despite its known limitations and toxicities, heparin use remains high because it is the only anticoagulant that can be controlled by an antidote, the polypeptide protamine [3].
  • Residues 150-183 are known to form a protamine-like domain required for packaging RNA, and residues 1-149 form the 'assembly domain' that polymerizes into capsids and, unusually for a capsid protein, is highly alpha-helical [4].
  • We now report the successful, cell-free isolation of an unusual, filterable agent prepared in protamine sulphate buffer from primary and animal-passaged lymphomas, which produces lymphomas with good efficiency when injected subcutaneously (s.c.) into newborn Syrian inbred (LSH) and random-bred (LVG) hamster [5].

Psychiatry related information on PRM1


High impact information on PRM1

  • Haploinsufficiency of protamine-1 or -2 causes infertility in mice [10].
  • Life-threatening reactions to intravenous protamine, administered to reverse heparin anticoagulation, have been reported with increasing frequency as a consequence of the escalating use of cardiac catheterization and coronary bypass surgery [11].
  • Functional coagulation studies revealed that the purified inhibitor had cofactor activity with antithrombin III that could be abolished by prior incubation with protamine sulfate or platelet factor 4 [12].
  • Single subcutaneous injections of 50 microng of protamine zinc somatostatin raised preprandial blood glucose levels to 83+/-3 mg per deciliter for four to five days although preprandial hormone levels were unchanged [13].
  • At the early protamine stage of testis development, polysomal and postribosomal supernatant fractions contain almost equal quantities of poly(A)+ protamine mRNA, but poly(A)- protamine mRNA was found almost entirely in the polysomes [14].

Chemical compound and disease context of PRM1


Biological context of PRM1

  • The spermatid-specific nucleoprotamine genes PRM1 and PRM2 and the transition protein gene TNP2 are clustered at a single site on human chromosome 16p13 [20].
  • The spermatids of men with severely deranged spermatogenesis exhibited significant lower PRM1 mRNA expression than in the other patient groups [21].
  • These results emphasize the role of PRM1 as a potentially critical factor in post-ICSI embryonic development [21].
  • We also observed one SNP in the 3' non-coding region of the PRM1 gene, and two SNPs within the intron of the PRM2 gene [22].
  • In mouse and human, the genes encoding protamines PRM1, PRM2 and transition protein TNP2 are found clustered together on chromosome 16 [23].

Anatomical context of PRM1

  • Analysis of the haploid-expressed human PRM1 --> PRM2 --> TNP2 genic domain has revealed two regions of attachment to the sperm nuclear matrix [24].
  • Spermatid PRM1 expression was lower in non-pregnant couples than in pregnant couples [21].
  • The cellular expression of PRM1 and PRM2 mRNAs in single testicular spermatids from 41 azoospermic patients (in whom testicular spermatozoa were subsequently recovered and submitted for TESE-ICSI) was determined by radioactive in situ hybridization [21].
  • Coordinate expression of the PRM1, PRM2, and TNP2 multigene locus in human testis [25].
  • CONCLUSION(S): In the present patient the breakpoint at 16p13.3 could have disrupted or harbored the PRM1, PRM2, or TNP2 genes responsible for the replacement of the histones involved in packaging the DNA into the sperm head [26].

Associations of PRM1 with chemical compounds

  • Previously, we have shown that the human PRM1 --> PRM2 --> TNP2 locus exists as a single chromatin domain bounded by two male germ cell-specific MARs, i.e. Matrix Attachment Regions [23].
  • The relative proportions of protamine 1, 2, and 3 were determined by scanning microdensitometry following electrophoresis of total protamine in polyacrylamide gels [27].
  • Human protamine P1 is highly homologous with the protamines isolated from bull, boar, ram and mouse sperm cells, but human protamine P2 shows a novel type of structure, although also here the dominant amino acids are arginine and cysteine [28].
  • The amino-acid sequence of protamine P1 was determined by analysing the intact protein and the fragments obtained by cyanogen bromide cleavage [28].
  • Purified MBP was studied for capacity to regulate the generation of classical and alternative-amplification pathway C3 convertases because previous studies have shown that other polycations (protamine, poly-L-lysine) and polyanions (heparin) may play important roles in regulating C activation [29].

Physical interactions of PRM1


Enzymatic interactions of PRM1

  • In addition, the kinase phosphorylates peptide epsilon and myelin basic protein with equal efficiency but phosphorylates Kemptide and protamine sulfate poorly [33].
  • Insulin-stimulated protamine kinase (cPK) and protein kinase C (PKC) phosphorylated eukaryotic protein synthesis initiation factor 4E (eIF-4E) on serine and threonine residues located on an identical tryptic fragment as judged by two-dimensional phosphopeptide mapping [34].

Regulatory relationships of PRM1


Other interactions of PRM1


Analytical, diagnostic and therapeutic context of PRM1


  1. A novel mechanism of protamine expression deregulation highlighted by abnormal protamine transcript retention in infertile human males with sperm protamine deficiency. Aoki, V.W., Liu, L., Carrell, D.T. Mol. Hum. Reprod. (2006) [Pubmed]
  2. Protamines and male infertility. Oliva, R. Hum. Reprod. Update (2006) [Pubmed]
  3. RNA aptamers as reversible antagonists of coagulation factor IXa. Rusconi, C.P., Scardino, E., Layzer, J., Pitoc, G.A., Ortel, T.L., Monroe, D., Sullenger, B.A. Nature (2002) [Pubmed]
  4. Visualization of a 4-helix bundle in the hepatitis B virus capsid by cryo-electron microscopy. Conway, J.F., Cheng, N., Zlotnick, A., Wingfield, P.T., Stahl, S.J., Steven, A.C. Nature (1997) [Pubmed]
  5. Unusual filterable oncogenic agent isolated from horizontally transmitted Syrian hamster lymphomas. Coggin, J.H., Oakes, J.E., Huebner, R.J., Gilden, R. Nature (1981) [Pubmed]
  6. Monitoring and management of anticoagulation in children requiring extracorporeal circulation. Malviya, S. Semin. Thromb. Hemost. (1997) [Pubmed]
  7. Further analysis of the resistance of the diabetic rat to d-amphetamine. Marshall, J.F. Pharmacol. Biochem. Behav. (1978) [Pubmed]
  8. Effect of warm heart surgery on perioperative management of patients undergoing urgent cardiac surgery. Kavanagh, B.P., Mazer, C.D., Panos, A., Lichtenstein, S.V. J. Cardiothorac. Vasc. Anesth. (1992) [Pubmed]
  9. Heparin rebound: a comparative study of protamine chloride and protamine sulfate in patients undergoing coronary artery bypass surgery. Kuitunen, A.H., Salmenperä, M.T., Heinonen, J., Rasi, V.P., Myllylä, G. J. Cardiothorac. Vasc. Anesth. (1991) [Pubmed]
  10. Haploinsufficiency of protamine-1 or -2 causes infertility in mice. Cho, C., Willis, W.D., Goulding, E.H., Jung-Ha, H., Choi, Y.C., Hecht, N.B., Eddy, E.M. Nat. Genet. (2001) [Pubmed]
  11. Association of protamine IgE and IgG antibodies with life-threatening reactions to intravenous protamine. Weiss, M.E., Nyhan, D., Peng, Z.K., Horrow, J.C., Lowenstein, E., Hirshman, C., Adkinson, N.F. N. Engl. J. Med. (1989) [Pubmed]
  12. Circulating heparan sulfate anticoagulant in a patient with a fatal bleeding disorder. Palmer, R.N., Rick, M.E., Rick, P.D., Zeller, J.A., Gralnick, H.R. N. Engl. J. Med. (1984) [Pubmed]
  13. Hypoglycemia of infancy and nesidioblastosis. Studies with somatostatin. Hirsch, H.J., Loo, S., Evans, N., Crigler, J.F., Filler, R.M., Gabbay, K.H. N. Engl. J. Med. (1977) [Pubmed]
  14. The distribution of poly(A)+ and poly(A)- protamine messenger RNA sequences in the developing trout testis. Iatrou, K., Dixon, G.H. Cell (1977) [Pubmed]
  15. Transgenic mice studies demonstrate a role for platelet factor 4 in thrombosis: dissociation between anticoagulant and antithrombotic effect of heparin. Eslin, D.E., Zhang, C., Samuels, K.J., Rauova, L., Zhai, L., Niewiarowski, S., Cines, D.B., Poncz, M., Kowalska, M.A. Blood (2004) [Pubmed]
  16. Selective thrombosis of tumor blood vessels in mammary adenocarcinoma implants in rats. Samoszuk, M.K., Su, M.Y., Najafi, A., Nalcioglu, O. Am. J. Pathol. (2001) [Pubmed]
  17. Influence of protamine on adhesion, chemotaxis and proliferation of human vascular smooth muscle cells. Cavalot, F., Russo, I., Mattiello, L., Anfossi, G., Massucco, P., Mularoni, E., Hahn, A.W., Trovati, M. Diabetologia (1997) [Pubmed]
  18. A pilot study indicating that bradykinin B2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass. Pretorius, M., Scholl, F.G., McFarlane, J.A., Murphey, L.J., Brown, N.J. Clin. Pharmacol. Ther. (2005) [Pubmed]
  19. Design of a genetic immunotoxin to eliminate toxin immunogenicity. Chen, S.Y., Zani, C., Khouri, Y., Marasco, W.A. Gene Ther. (1995) [Pubmed]
  20. Characterization of a human locus in transition. Nelson, J.E., Krawetz, S.A. J. Biol. Chem. (1994) [Pubmed]
  21. Cellular expression of protamine 1 and 2 transcripts in testicular spermatids from azoospermic men submitted to TESE-ICSI. Mitchell, V., Steger, K., Marchetti, C., Herbaut, J.C., Devos, P., Rigot, J.M. Mol. Hum. Reprod. (2005) [Pubmed]
  22. Single nucleotide polymorphisms in the protamine-1 and -2 genes of fertile and infertile human male populations. Tanaka, H., Miyagawa, Y., Tsujimura, A., Matsumiya, K., Okuyama, A., Nishimune, Y. Mol. Hum. Reprod. (2003) [Pubmed]
  23. Conservation of the PRM1 --> PRM2 --> TNP2 domain. Wykes, S.M., Krawetz, S.A. DNA Seq. (2003) [Pubmed]
  24. Nuclear matrix interactions within the sperm genome. Kramer, J.A., Krawetz, S.A. J. Biol. Chem. (1996) [Pubmed]
  25. Coordinate expression of the PRM1, PRM2, and TNP2 multigene locus in human testis. Wykes, S.M., Nelson, J.E., Visscher, D.W., Djakiew, D., Krawetz, S.A. DNA Cell Biol. (1995) [Pubmed]
  26. Reciprocal translocation t(7;16)(q21.2;p13.3) in an infertile man. Mikelsaar, R., Pauklin, M., Lissitsina, J., Punab, M. Fertil. Steril. (2006) [Pubmed]
  27. Human male infertility may be due to a decrease of the protamine P2 content in sperm chromatin. Belokopytova, I.A., Kostyleva, E.I., Tomilin, A.N., Vorob'ev, V.I. Mol. Reprod. Dev. (1993) [Pubmed]
  28. Isolation and amino-acid sequence analysis of human sperm protamines P1 and P2. Occurrence of two forms of protamine P2. Ammer, H., Henschen, A., Lee, C.H. Biol. Chem. Hoppe-Seyler (1986) [Pubmed]
  29. Eosinophil granule major basic protein regulates generation of classical and alternative-amplification pathway C3 convertases in vitro. Weiler, J.M., Gleich, G.J. J. Immunol. (1988) [Pubmed]
  30. Effect of heparin anticoagulation on neutrophil adhesion molecules and release of IL8: C3 is not essential. El Habbal, M.H., Smith, L., Elliott, M.J., Strobel, S. Cardiovasc. Res. (1995) [Pubmed]
  31. Transport of human recombinant brain-derived neurotrophic factor (BDNF) through the rat blood-brain barrier in vivo using vector-mediated peptide drug delivery. Pardridge, W.M., Kang, Y.S., Buciak, J.L. Pharm. Res. (1994) [Pubmed]
  32. An unusual form of purifying selection in a sperm protein. Rooney, A.P., Zhang, J., Nei, M. Mol. Biol. Evol. (2000) [Pubmed]
  33. Phosphatidylinositol 3-kinase-dependent activation of protein kinase C-zeta in bacterial lipopolysaccharide-treated human monocytes. Herrera-Velit, P., Knutson, K.L., Reiner, N.E. J. Biol. Chem. (1997) [Pubmed]
  34. Phosphorylation of eukaryotic protein synthesis initiation factor 4E by insulin-stimulated protamine kinase. Makkinje, A., Xiong, H., Li, M., Damuni, Z. J. Biol. Chem. (1995) [Pubmed]
  35. Expression of the TAR RNA binding protein in human testis. Siffroi, J.P., Pawlak, A., Alfonsi, M.F., Troalen, F., Guellaen, G., Dadoune, J.P. Mol. Hum. Reprod. (2001) [Pubmed]
  36. Protamine inhibits tissue factor-initiated extrinsic coagulation. Chu, A.J., Wang, Z.G., Raicu, M., Beydoun, S., Ramos, N. Br. J. Haematol. (2001) [Pubmed]
  37. Inhibitory effect of platelet factor 4 on human erythroleukemic cells is dependent on cell surface heparan sulfate. Maurer, A.M., Han, Z.C., Dhermy, D., Briere, J. J. Lab. Clin. Med. (1996) [Pubmed]
  38. Protamine enhances fibrinolysis by decreasing clot strength: role of tissue factor-initiated thrombin generation. Nielsen, V.G. Ann. Thorac. Surg. (2006) [Pubmed]
  39. Autocrine activities of basic fibroblast growth factor: regulation of endothelial cell movement, plasminogen activator synthesis, and DNA synthesis. Sato, Y., Rifkin, D.B. J. Cell Biol. (1988) [Pubmed]
  40. Nuclear matrix interactions at the human protamine domain: a working model of potentiation. Martins, R.P., Ostermeier, G.C., Krawetz, S.A. J. Biol. Chem. (2004) [Pubmed]
  41. A haploid expressed gene cluster exists as a single chromatin domain in human sperm. Choudhary, S.K., Wykes, S.M., Kramer, J.A., Mohamed, A.N., Koppitch, F., Nelson, J.E., Krawetz, S.A. J. Biol. Chem. (1995) [Pubmed]
  42. Genesis of a novel human sequence from the protamine PRM1 gene. Kramer, J.A., Krawetz, S.A. Comp. Biochem. Physiol. C, Pharmacol. Toxicol. Endocrinol. (1998) [Pubmed]
  43. Electron microscopic in situ hybridization study of simultaneous expression of TNP1 and PRM1 genes in human spermatids. Siffroi, J.P., Alfonsi, M.F., Dadoune, J.P. Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia. (1998) [Pubmed]
  44. Cyproterone acetate affects protamine gene expression in the testis of adult male rat. Aleem, M., Padwal, V., Choudhari, J., Balasinor, N., Parte, P., Gill-Sharma, M. Contraception. (2005) [Pubmed]
  45. Chromosomal localization of the human protamine genes, PRM1 and PRM2, to 16p13.3 by in situ hybridization. Viguié, F., Domenjoud, L., Rousseau-Merck, M.F., Dadoune, J.P., Chevaillier, P. Hum. Genet. (1990) [Pubmed]
  46. Sperm nuclear histone to protamine ratio in fertile and infertile men: evidence of heterogeneous subpopulations of spermatozoa in the ejaculate. Zhang, X., Gabriel, M.S., Zini, A. J. Androl. (2006) [Pubmed]
  47. On the expression of protamine genes in the testis of man and other mammals. Domenjoud, L., Kremling, H., Burfeind, P., Maier, W.M., Engel, W. Andrologia (1991) [Pubmed]
  48. Sequence analysis of the conserved protamine gene cluster shows that it contains a fourth expressed gene. Schlüter, G., Celik, A., Obata, R., Schlicker, M., Hofferbert, S., Schlung, A., Adham, I.M., Engel, W. Mol. Reprod. Dev. (1996) [Pubmed]
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