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Sökning: WFRF:(Yee C) > (1995-1999) > Four novel mutation...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00006389naa a2200841 4500
001oai:lup.lub.lu.se:9950a27a-5d41-43bd-ac15-eedfffda0bc3
003SwePub
008161125s1996 | |||||||||||000 ||eng|
0247 a https://lup.lub.lu.se/record/9950a27a-5d41-43bd-ac15-eedfffda0bc32 URI
040 a (SwePub)lu
041 a engb eng
042 9 SwePub
072 7a art2 swepub-publicationtype
072 7a ref2 swepub-contenttype
1001 a Mikkola, Hanna4 aut
2451 0a Four novel mutations in deficiency of coagulation factor XIII: Consequences to expression and structure of the A-subunit
264 1c 1996
300 a 11 s.
520 a The characterization of naturally occurring mutations is one way to approach functionally significant domains of polypeptides. About 10 mutations have been reported in factor XIII (FXIII) A-subunit deficiency, but very little is known about the effects of the mutations on the expression or the structure of this enzyme. In this study, the recent crystallization of FXIII A-subunit and determination of the three-dimensional model were used for the first time to pursue the structural consequences of mutations in the A- subunit. The molecular analysis of four families from Sweden, Germany, and Denmark revealed four previously unreported point mutations. Three of the mutations were missense mutations, Arg326 → Gln, Arg252 → Ile, and Leu498 → Pro, and one was a nonsense mutation, a deletion of thymidine in codon for Phe8 resulting in early frameshift and premature termination of the polypeptide chain. In the case of the nonsense mutation, delT Phe8, the steady-state mRNA level of FXIII A-subunit was reduced, as quantitated by reverse transcriptase-polymerase chain reaction and solid-phase minisequencing. In contrast, none of the missense mutations affected mRNA levels, indicating the possible translation of the mutant polypeptides. However, by enzyme-linked immunosorbent analysis and immunofluorescence, all the patients demonstrated a complete lack of detectable factor XIIIA antigen in their platelets. In the structural analysis, we included the mutations described in this work and the Met242 → Thr mutation reported earlier by us. Interestingly, in the three-dimensional model, all four missense mutations are localized in the evolutionarily conserved catalytic core domain. The substitutions are at least 15 Å away from the catalytic cleft and do not affect any of the residues known to be directly involved in the enzymetic reaction. The structural analyses suggest that the mutations are most likely interfering with proper folding and stability of the protein, which is in agreement with the observed absence of detectable FXIIIA antigen. Arg326, Arg252, and Met242 are all buried within the molecule. The Arg326 → Gln and Arg252 → Ile mutations are substitutions of smaller, neutral amino acids for large, charged residues. They disrupt the electrostatic balance and hydrogen- bonding interactions in structurally significant areas. The Met242 → Thr mutation is located in the same region of the core domain as the Arg252 → Ile site and is expected to have a destabilizing effect due to an introduction of a smaller, polar residue in a tightly packed hydrophobic pocket. The substitution of proline for Leu498 is predicted to cause unfavorable interatomic contacts and a disruption of the alpha-helix mainchain hydrogen-bonding pattern; it is likely to form a kink in the helix next to the dimer interface and is expected to impair proper dimerization of the A-subunits. In the case of all four missense mutations studied, the knowledge achieved from the three-dimensional model of crystallized FXIII A- subunit provides essential information about the structural significance of the specific residues and aids in understanding the biologic consequences of the mutations observed at the cellular level.
650 7a NATURVETENSKAPx Biologix Biokemi och molekylärbiologi0 (SwePub)106022 hsv//swe
650 7a NATURAL SCIENCESx Biological Sciencesx Biochemistry and Molecular Biology0 (SwePub)106022 hsv//eng
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Annan klinisk medicin0 (SwePub)302992 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Other Clinical Medicine0 (SwePub)302992 hsv//eng
653 a arginine
653 a blood clotting factor 13a
653 a glutamine
653 a isoleucine
653 a leucine
653 a messenger RNA
653 a methionine
653 a proline
653 a adolescent
653 a adult
653 a alpha chain
653 a article
653 a blood clotting factor 13 deficiency
653 a child
653 a clinical article
653 a clinical protocol
653 a codon
653 a Denmark
653 a enzyme linked immunosorbent assay
653 a family study
653 a female
653 a frameshift mutation
653 a gene expression
653 a genetic analysis
653 a Germany
653 a human
653 a hydrogen bond
653 a immunofluorescence
653 a male
653 a missense mutation
653 a mutation
653 a nonsense mutation
653 a point mutation
653 a priority journal
653 a protein folding
653 a protein stability
653 a reverse transcription polymerase chain reaction
653 a Sweden
7001 a Yee, Vivien C.4 aut
7001 a Syrjälä, Martti4 aut
7001 a Seitz, Rainer4 aut
7001 a Egbring, Rudolf4 aut
7001 a Petrini, Pia4 aut
7001 a Ljung, Rolfu Lund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Pediatrisk hematologi,Forskargrupper vid Lunds universitet,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,Paediatric Haematology Research Unit,Lund University Research Groups4 aut0 (Swepub:lu)pedi-rlj
7001 a Ingerslev, Jorgen4 aut
7001 a Teller, David C.4 aut
7001 a Palotie, Aarnou University of Helsinki4 aut
7102 a Pediatrik, Lundb Sektion V4 org
7730 t Bloodg 87:1, s. 141-151q 87:1<141-151x 1528-0020
8564 8u https://lup.lub.lu.se/record/9950a27a-5d41-43bd-ac15-eedfffda0bc3

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