title: Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity.
abstract: Kallikrein is synthesized in the distal tubules and produces kinins, which are involved in the regulation of vascular tone in the kidney. Urinary kallikrein activity has been reported to be partly inherited and to be reduced in essential hypertension. In a systematic search for molecular variants of the human kallikrein gene, nine single-nucleotide polymorphisms were identified. Five of those polymorphisms, including two nonsynonymous substitutions in exon 3, i.e., Arg53His (allelic frequency in Caucasian subjects, 0.03) and Gln121Glu (allelic frequency, 0.33), were studied in a normotensive group and two independent hypertensive groups for which 24-h urinary kallikrein activity had been measured. A significant decrease in urinary kallikrein activity was observed for the subjects who were heterozygous for the Arg53His polymorphism, compared with the other subjects. This finding was consistent in the two hypertensive groups and was observed with several kallikrein enzymatic assays. The Gln121Glu polymorphism and the other polymorphisms were not associated with changes in urinary kallikrein activity. None of the polymorphisms was associated with hypertension. Recombinant kallikrein variants were synthesized and enzymatically characterized, using native kininogen and kininogen-derived synthetic peptide substrates. No important effect was observed after Gln121 mutation, but there was a major decrease in enzyme activity when Arg53 was replaced by histidine. A model of kallikrein derived from crystallographic data suggested that Arg53 can affect substrate binding. The identification of a subset of subjects with genetically reduced kallikrein activity as a result of an amino acid mutation could facilitate analysis of the role of the kallikrein-kinin system in renal and vascular diseases.
authors.affiliation: *INSERM U367, Paris VI-University, France; Department of Genetics, Georges Pompidou European Hospital and INSERM U36, Paris, France; INSERM-François Rabelais University U10, Tours, France; Howard Hughes Institute of Human Genetics, University of Utah, Salt Lake City, Utah; and Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rola
authors.initials: R
authors.lastname: Slim
authors.affiliation: *INSERM U367, Paris VI-University, France; Department of Genetics, Georges Pompidou European Hospital and INSERM U36, Paris, France; INSERM-François Rabelais University U10, Tours, France; Howard Hughes Institute of Human Genetics, University of Utah, Salt Lake City, Utah; and Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Florence
authors.initials: F
authors.lastname: Torremocha
authors.affiliation: *INSERM U367, Paris VI-University, France; Department of Genetics, Georges Pompidou European Hospital and INSERM U36, Paris, France; INSERM-François Rabelais University U10, Tours, France; Howard Hughes Institute of Human Genetics, University of Utah, Salt Lake City, Utah; and Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Thierry
authors.initials: T
authors.lastname: Moreau
authors.affiliation: *INSERM U367, Paris VI-University, France; Department of Genetics, Georges Pompidou European Hospital and INSERM U36, Paris, France; INSERM-François Rabelais University U10, Tours, France; Howard Hughes Institute of Human Genetics, University of Utah, Salt Lake City, Utah; and Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Anne
authors.initials: A
authors.lastname: Pizard
authors.affiliation: *INSERM U367, Paris VI-University, France; Department of Genetics, Georges Pompidou European Hospital and INSERM U36, Paris, France; INSERM-François Rabelais University U10, Tours, France; Howard Hughes Institute of Human Genetics, University of Utah, Salt Lake City, Utah; and Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.affiliation: *INSERM U367, Paris VI-University, France; Department of Genetics, Georges Pompidou European Hospital and INSERM U36, Paris, France; INSERM-François Rabelais University U10, Tours, France; Howard Hughes Institute of Human Genetics, University of Utah, Salt Lake City, Utah; and Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Albert
authors.initials: A
authors.lastname: Vuagnat
authors.affiliation: *INSERM U367, Paris VI-University, France; Department of Genetics, Georges Pompidou European Hospital and INSERM U36, Paris, France; INSERM-François Rabelais University U10, Tours, France; Howard Hughes Institute of Human Genetics, University of Utah, Salt Lake City, Utah; and Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Williams
authors.affiliation: *INSERM U367, Paris VI-University, France; Department of Genetics, Georges Pompidou European Hospital and INSERM U36, Paris, France; INSERM-François Rabelais University U10, Tours, France; Howard Hughes Institute of Human Genetics, University of Utah, Salt Lake City, Utah; and Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Francis
authors.initials: F
authors.lastname: Gauthier
authors.affiliation: *INSERM U367, Paris VI-University, France; Department of Genetics, Georges Pompidou European Hospital and INSERM U36, Paris, France; INSERM-François Rabelais University U10, Tours, France; Howard Hughes Institute of Human Genetics, University of Utah, Salt Lake City, Utah; and Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.affiliation: *INSERM U367, Paris VI-University, France; Department of Genetics, Georges Pompidou European Hospital and INSERM U36, Paris, France; INSERM-François Rabelais University U10, Tours, France; Howard Hughes Institute of Human Genetics, University of Utah, Salt Lake City, Utah; and Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: François
authors.initials: F
authors.lastname: Alhenc-Gelas
mesh_terms: D000483:Alleles; D001483:Base Sequence / Q000235:genetics; D005787:Gene Frequency; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007610:Kallikreins / Q000235:genetics* / Q000652:urine*; D009154:Mutation / Q000502:physiology; D009994:Osmolar Concentration; D011110:Polymorphism, Genetic / Q000502:physiology*; D018807:Polymorphism, Single-Stranded Conformational
chemical_list: D007610:Kallikreins