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Journal of Applied Genetics

, Volume 49, Issue 3, pp 283–295 | Cite as

Two novelCOL1A1 mutations in patients with osteogenesis imperfecta (OI) affect the stability of the collagen type I triple-helix

  • Joanna Witecka
  • Aleksandra M. Auguściak-Duma
  • Anna Kruczek
  • Anna Szydło
  • Marta Lesiak
  • Maria Krzak
  • Jacek J. Pietrzyk
  • Minna Männikkö
  • Aleksander L. Sieroń
Original Article

Abstract

Osteogenesis imperfecta (OI) is a bone dysplasia caused by mutations in theCOL1A1 andCOL1A2 genes. Although the condition has been intensely studied for over 25 years and recently over 800 novel mutations have been published, the relation between the location of mutations and clinical manifestation is poorly understood. Here we report missense mutations inCOL1A1 of several OI patients. Two novel mutations were found in the D1 period. One caused a substitution of glycine 200 by valine at the N-terminus of D1 in OI type I/IV, lowering collagen stability by 50% at 34°C. The other one was a substitution of valine 349 by phenylalanine at the C-terminus of D1 in OI type I, lowering collagen stability at 37.5°C. Two other mutations, reported before, changed amino residues in D4. One was a lethal substitution changing glycine 866 to serine in genetically identical twins with OI type II. That mutated amino acid was near the border of D3 and D4. The second mutation changed glycine 1040 to serine located at the border of D4 and D0.4, in a proband manifesting OI type III, and lowered collagen stability at 39°C (2°C lower than normal). Our results confirm the hypothesis on a critical role of the D1 and D4 regions in stabilization of the collagen triple-helix. The defect in D1 seemed to produce a milder clinical type of OI, whereas the defect in the C-terminal end of collagen type caused the more severe or lethal types of OI.

Keywords

collagen D-periods collagen mutations collagen thermal stability heteroduplex analysis osteogenesis imperfecta surveyor endonuclease 

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Copyright information

© Institute of Plant Genetics, Polish Academy of Sciences, Poznan 2008

Authors and Affiliations

  • Joanna Witecka
    • 1
    • 3
  • Aleksandra M. Auguściak-Duma
    • 1
    • 3
  • Anna Kruczek
    • 2
  • Anna Szydło
    • 1
    • 3
  • Marta Lesiak
    • 1
    • 3
  • Maria Krzak
    • 1
    • 3
  • Jacek J. Pietrzyk
    • 2
  • Minna Männikkö
    • 4
  • Aleksander L. Sieroń
    • 1
    • 3
  1. 1.Department of General and Molecular Biology and GeneticsMedical University of SilesiaKatowicePoland
  2. 2.Department of Genetics, Polish-American Children’s Hospital, Collegium MedicumJagiellonian UniversityKrakowPoland
  3. 3.Center of Excellence for Research and Teaching of Matrix Biology and NanotechnologyNetwork of CoE BioMedTech SilesiaPoland
  4. 4.Collagen Research Unit, Biocenter and Department of Medical Biochemistry and Molecular BiologyUniversity of OuluFinland

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