DOI: 10.1073/pnas.080517697. Rab geranylgeranyl transferase α mutation in the <i>gunmetal</i> mouse reduces Rab prenylation and platelet synthesis

Rab geranylgeranyl transferase α mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis

10.1073/pnas.080517697

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Few molecular events important to platelet biogenesis have been identified. Mice homozygous for the spontaneous, recessive mutation gunmetal ( gm ) have prolonged bleeding, thrombocytopenia, and reduced platelet α- and δ-granule contents. Here we show by positional cloning that gm results from a G→A substitution mutation in a splice acceptor site within the α-subunit of Rab geranylgeranyl transferase ( Rabggta ), an enzyme that attaches geranylgeranyl groups to Rab proteins. Most Rabggta mRNAs from gm tissues skipped exon 1 and lacked a start codon. Rabggta protein and Rab geranylgeranyl transferase (GGTase) activity were reduced 4-fold in gm platelets. Geranylgeranylation and membrane association of Rab27, a Rab GGTase substrate, were significantly decreased in gm platelets. These findings indicate that geranylgeranylation of Rab GTPases is critical for hemostasis. Rab GGTase inhibition may represent a new treatment for thrombocytosis and clotting disorders.

Bibliography

Detter, J. C., Zhang, Q., Mules, E. H., Novak, E. K., Mishra, V. S., Li, W., McMurtrie, E. B., Tchernev, V. T., Wallace, M. R., Seabra, M. C., Swank, R. T., & Kingsmore, S. F. (2000). Rab geranylgeranyl transferase Î± mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis. Proceedings of the National Academy of Sciences, 97(8), 4144â4149.

Authors 12

John C. Detter (first)
Qing Zhang (additional)
Emilie H. Mules (additional)
Edward K. Novak (additional)
Vishnu S. Mishra (additional)
Wei Li (additional)
Elzbieta B. McMurtrie (additional)
Velizar T. Tchernev (additional)
Margaret R. Wallace (additional)
Miguel C. Seabra (additional)
Richard T. Swank (additional)
Stephen F. Kingsmore (additional)

References 29 Referenced 142

10.1136/bmj.308.6921.81
10.1182/blood.V81.10.2626.2626
10.1182/blood.V85.7.1781.bloodjournal8571781
E L Green Genetics and Probabilities in Animal Breeding Experiments (Macmillan, New York), pp. 77–113 (1981). (10.1007/978-1-349-04904-2_4) / Genetics and Probabilities in Animal Breeding Experiments by Green E L (1981)
10.1093/nar/26.17.4091
Detter J. C. Mishra V. S. & Kingsmore S. F. (2000) Biotechniques in press.
10.1182/blood.V78.8.2036.2036
10.1016/S0021-9258(19)50329-5
10.1074/jbc.270.41.24420
10.1007/s003359900055
10.1007/BF00210743
10.1016/S0898-6568(97)00120-4
10.1016/S0021-9258(19)49740-8
10.1016/S0021-9258(18)93008-5
10.1042/bj3330497
10.1074/jbc.271.10.5289
10.1006/bmme.1996.2559
10.1006/abio.1995.1086
10.1016/0092-8674(92)90253-9
10.1126/science.8380507
10.1016/S0021-9258(17)42142-9
10.1093/hmg/6.6.851
10.1016/S0955-0674(97)80025-7
10.1083/jcb.147.6.1299
10.1074/jbc.273.35.22161
10.1111/j.1600-0749.1998.tb00713.x
10.1182/blood.V66.6.1309.1309
10.1016/S0950-3536(97)80054-6
10.1182/blood.V54.6.1296.1296

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:38 a.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 5:21 p.m.)
Indexed	4 months, 3 weeks ago (April 7, 2025, 10:03 a.m.)
Issued	25 years, 5 months ago (March 28, 2000)
Published	25 years, 5 months ago (March 28, 2000)
Published Online	25 years, 5 months ago (March 28, 2000)
Published Print	25 years, 4 months ago (April 11, 2000)

Funders 0

None

BibTeX

@article{Detter_2000, title={Rab geranylgeranyl transferase α mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis}, volume={97}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.080517697}, DOI={10.1073/pnas.080517697}, number={8}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Detter, John C. and Zhang, Qing and Mules, Emilie H. and Novak, Edward K. and Mishra, Vishnu S. and Li, Wei and McMurtrie, Elzbieta B. and Tchernev, Velizar T. and Wallace, Margaret R. and Seabra, Miguel C. and Swank, Richard T. and Kingsmore, Stephen F.}, year={2000}, month=mar, pages={4144–4149} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        4,
        7
      ]
    ],
    "date-time": "2025-04-07T14:03:04Z",
    "timestamp": 1744034584474
  },
  "reference-count": 29,
  "publisher": "Proceedings of the National Academy of Sciences",
  "issue": "8",
  "content-domain": {
    "domain": [
      "www.pnas.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2000,
        4,
        11
      ]
    ]
  },
  "abstract": "<jats:p>\n            Few molecular events important to platelet biogenesis have been identified. Mice homozygous for the spontaneous, recessive mutation\n            <jats:italic>gunmetal</jats:italic>\n            (\n            <jats:italic>gm</jats:italic>\n            ) have prolonged bleeding, thrombocytopenia, and reduced platelet \u03b1- and \u03b4-granule contents. Here we show by positional cloning that\n            <jats:italic>gm</jats:italic>\n            results from a G\u2192A substitution mutation in a splice acceptor site within the \u03b1-subunit of Rab geranylgeranyl transferase (\n            <jats:italic>Rabggta</jats:italic>\n            ), an enzyme that attaches geranylgeranyl groups to Rab proteins. Most Rabggta mRNAs from\n            <jats:italic>gm</jats:italic>\n            tissues skipped exon 1 and lacked a start codon. Rabggta protein and Rab geranylgeranyl transferase (GGTase) activity were reduced 4-fold in\n            <jats:italic>gm</jats:italic>\n            platelets. Geranylgeranylation and membrane association of Rab27, a Rab GGTase substrate, were significantly decreased in\n            <jats:italic>gm</jats:italic>\n            platelets. These findings indicate that geranylgeranylation of Rab GTPases is critical for hemostasis. Rab GGTase inhibition may represent a new treatment for thrombocytosis and clotting disorders.\n          </jats:p>",
  "DOI": "10.1073/pnas.080517697",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2002,
        7,
        26
      ]
    ],
    "date-time": "2002-07-26T14:38:21Z",
    "timestamp": 1027694301000
  },
  "page": "4144-4149",
  "update-policy": "http://dx.doi.org/10.1073/pnas.cm10313",
  "source": "Crossref",
  "is-referenced-by-count": 142,
  "title": "Rab geranylgeranyl transferase \u03b1 mutation in the\n            <i>gunmetal</i>\n            mouse reduces Rab prenylation and platelet synthesis",
  "prefix": "10.1073",
  "volume": "97",
  "author": [
    {
      "given": "John C.",
      "family": "Detter",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    },
    {
      "given": "Qing",
      "family": "Zhang",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    },
    {
      "given": "Emilie H.",
      "family": "Mules",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    },
    {
      "given": "Edward K.",
      "family": "Novak",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    },
    {
      "given": "Vishnu S.",
      "family": "Mishra",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    },
    {
      "given": "Wei",
      "family": "Li",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    },
    {
      "given": "Elzbieta B.",
      "family": "McMurtrie",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    },
    {
      "given": "Velizar T.",
      "family": "Tchernev",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    },
    {
      "given": "Margaret R.",
      "family": "Wallace",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    },
    {
      "given": "Miguel C.",
      "family": "Seabra",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    },
    {
      "given": "Richard T.",
      "family": "Swank",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    },
    {
      "given": "Stephen F.",
      "family": "Kingsmore",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Carlton and Elm Streets, Buffalo, NY 14263; Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom; and Molecular Staging Inc., 66..."
        }
      ]
    }
  ],
  "member": "341",
  "published-online": {
    "date-parts": [
      [
        2000,
        3,
        28
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_3_2_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1136/bmj.308.6921.81"
    },
    {
      "key": "e_1_3_2_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V81.10.2626.2626"
    },
    {
      "key": "e_1_3_2_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V85.7.1781.bloodjournal8571781"
    },
    {
      "key": "e_1_3_2_4_2",
      "doi-asserted-by": "crossref",
      "first-page": "77",
      "DOI": "10.1007/978-1-349-04904-2_4",
      "volume-title": "Genetics and Probabilities in Animal Breeding Experiments",
      "author": "Green E L",
      "year": "1981",
      "unstructured": "E L Green Genetics and Probabilities in Animal Breeding Experiments (Macmillan, New York), pp. 77\u2013113 (1981)."
    },
    {
      "key": "e_1_3_2_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/nar/26.17.4091"
    },
    {
      "key": "e_1_3_2_6_2",
      "unstructured": "Detter J. C. Mishra V. S. & Kingsmore S. F. (2000) Biotechniques in press."
    },
    {
      "key": "e_1_3_2_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V78.8.2036.2036"
    },
    {
      "key": "e_1_3_2_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(19)50329-5"
    },
    {
      "key": "e_1_3_2_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.270.41.24420"
    },
    {
      "key": "e_1_3_2_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/s003359900055"
    },
    {
      "key": "e_1_3_2_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/BF00210743"
    },
    {
      "key": "e_1_3_2_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0898-6568(97)00120-4"
    },
    {
      "key": "e_1_3_2_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(19)49740-8"
    },
    {
      "key": "e_1_3_2_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(18)93008-5"
    },
    {
      "key": "e_1_3_2_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1042/bj3330497"
    },
    {
      "key": "e_1_3_2_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.271.10.5289"
    },
    {
      "key": "e_1_3_2_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/bmme.1996.2559"
    },
    {
      "key": "e_1_3_2_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/abio.1995.1086"
    },
    {
      "key": "e_1_3_2_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(92)90253-9"
    },
    {
      "key": "e_1_3_2_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.8380507"
    },
    {
      "key": "e_1_3_2_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(17)42142-9"
    },
    {
      "key": "e_1_3_2_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/6.6.851"
    },
    {
      "key": "e_1_3_2_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0955-0674(97)80025-7"
    },
    {
      "key": "e_1_3_2_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.147.6.1299"
    },
    {
      "key": "e_1_3_2_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.273.35.22161"
    },
    {
      "key": "e_1_3_2_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1111/j.1600-0749.1998.tb00713.x"
    },
    {
      "key": "e_1_3_2_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V66.6.1309.1309"
    },
    {
      "key": "e_1_3_2_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0950-3536(97)80054-6"
    },
    {
      "key": "e_1_3_2_29_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V54.6.1296.1296"
    }
  ],
  "container-title": "Proceedings of the National Academy of Sciences",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://pnas.org/doi/pdf/10.1073/pnas.080517697",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2022,
        4,
        12
      ]
    ],
    "date-time": "2022-04-12T21:21:56Z",
    "timestamp": 1649798516000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://pnas.org/doi/full/10.1073/pnas.080517697"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2000,
        3,
        28
      ]
    ]
  },
  "references-count": 29,
  "journal-issue": {
    "issue": "8",
    "published-print": {
      "date-parts": [
        [
          2000,
          4,
          11
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1073/pnas.080517697"
  ],
  "URL": "http://dx.doi.org/10.1073/pnas.080517697",
  "relation": {},
  "ISSN": [
    "0027-8424",
    "1091-6490"
  ],
  "subject": [],
  "container-title-short": "Proc. Natl. Acad. Sci. U.S.A.",
  "published": {
    "date-parts": [
      [
        2000,
        3,
        28
      ]
    ]
  },
  "assertion": [
    {
      "value": "1999-11-29",
      "order": 0,
      "name": "received",
      "label": "Received",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2000-03-28",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}