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Identification and characterization of two missense mutations causing factor XIIIA deficiency

Kangsadalampai, S; Chelvanayagam, Gareth; Baker, Rohan; Kuperan, Ponnudarai; Board, Philip

Description

In this study, two amino acid substitutions. Arg260His and Val414Phe, have been identified in the factor XIIIA subunits of factor XIII deficient patients of Syrian and Indian descent, respectively. To confirm the deleterious effects of these substitutions, both variant sequences have been engineered into cDNA clones and the mutant enzymes expressed in yeast. Determination of the transglutaminase activity and immuno detection of the mutant enzymes together with mRNA hybridization revealed that...[Show more]

dc.contributor.authorKangsadalampai, S
dc.contributor.authorChelvanayagam, Gareth
dc.contributor.authorBaker, Rohan
dc.contributor.authorKuperan, Ponnudarai
dc.contributor.authorBoard, Philip
dc.date.accessioned2015-12-13T23:25:03Z
dc.identifier.issn0007-1048
dc.identifier.urihttp://hdl.handle.net/1885/92495
dc.description.abstractIn this study, two amino acid substitutions. Arg260His and Val414Phe, have been identified in the factor XIIIA subunits of factor XIII deficient patients of Syrian and Indian descent, respectively. To confirm the deleterious effects of these substitutions, both variant sequences have been engineered into cDNA clones and the mutant enzymes expressed in yeast. Determination of the transglutaminase activity and immuno detection of the mutant enzymes together with mRNA hybridization revealed that the mutations dramatically reduce both the catalytic activity and the level of enzyme expressed in yeast. The mutations Arg260His and Val414Phe occur within the 'core' domain of the enzyme. Computer modelling of the mutant enzymes reveals that the substitution of the Arg260 by His results in the loss of a conserved electrostatic interaction whereas the effect of the Val414Phe substitution is a consequence of the large increase in side-chain volume. Although both mutations do not effect the active site directly, they are predicted to reduce the stability of the enzyme. The effects of these two amino acid substitutions on enzyme expression and three-dimensional structure strongly confirm that residues which are located outside of the active site can have a significant effect on protein stability and function.
dc.publisherBlackwell Publishing Ltd
dc.sourceBritish Journal of Haematology
dc.subjectKeywords: arginine; blood clotting factor 8a; complementary DNA; histidine; mutant protein; phenylalanine; protein glutamine gamma glutamyltransferase; valine; adult; amino acid substitution; article; case report; computer model; controlled study; enzyme stability; Deficiency; Factor XIIIA subunit; Missense mutations
dc.titleIdentification and characterization of two missense mutations causing factor XIIIA deficiency
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume104
dc.date.issued1999
local.identifier.absfor060403 - Developmental Genetics (incl. Sex Determination)
local.identifier.ariespublicationMigratedxPub23612
local.type.statusPublished Version
local.contributor.affiliationKangsadalampai, S, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationChelvanayagam, Gareth, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationBaker, Rohan, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationKuperan, Ponnudarai, National University Hospital
local.contributor.affiliationBoard, Philip, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue1
local.bibliographicCitation.startpage37
local.bibliographicCitation.lastpage43
local.identifier.doi10.1046/j.1365-2141.1999.01145.x
dc.date.updated2015-12-12T09:23:09Z
local.identifier.scopusID2-s2.0-0032928266
CollectionsANU Research Publications

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