Reference : Type I collagen triplet duplication mutation in lethal osteogenesis imperfecta shifts...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Type I collagen triplet duplication mutation in lethal osteogenesis imperfecta shifts register of alpha chains throughout the helix and disrupts incorporation of mutant helices into fibrils and extracellular matrix.
Cabral, Wayne A [>National Institutes of Health, Bethesda, Maryland - USA > > >Section on connective Tissue Disorders > > >]
Mertts, Marianna V [>National Institutes of Health, Bethesda, Maryland -USA > > Section on Physical Biochemistry > > >]
Makareeva, Elena [>National Institutes of Health, Bethesda, Maryland - USA > > >Section on Physical Biochemistry > > >]
Colige, Alain mailto [Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire des tissus conjonctifs >]
Tekin, Mustafa [>MCV/VCU, Richmond, Virginia > > >Dpt of Human Genetics > > >]
Pandya, Arti [>MCV/VCU, Richmond, Virginia > > >Dpt of Human Genetics > > >]
Leikin, Sergey [>National Institutes of Health, Bethesda, Maryland- USA > > >Section on Physical Biochemistry > > >]
Marini, Joan C [>National Institutes of Health, Bethesda, Maryland - USA > > >Section on Connective Tissue Disorders > > >]
Journal of Biological Chemistry
American Society for Biochemistry and Molecular Biology
Yes (verified by ORBi)
[en] Adult ; Amino Acid Sequence ; Base Sequence ; Collagen Type I/chemistry/genetics ; Extracellular Matrix/metabolism ; Female ; Humans ; Male ; Molecular Sequence Data ; Mutation/genetics ; Osteogenesis Imperfecta/genetics/metabolism ; Procollagen/metabolism ; Repetitive Sequences, Amino Acid/genetics
[en] The majority of collagen mutations causing osteogenesis imperfecta (OI) are glycine substitutions that disrupt formation of the triple helix. A rare type of collagen mutation consists of a duplication or deletion of one or two Gly-X-Y triplets. These mutations shift the register of collagen chains with respect to each other in the helix but do not interrupt the triplet sequence, yet they have severe clinical consequences. We investigated the effect of shifting the register of the collagen helix by a single Gly-X-Y triplet on collagen assembly, stability, and incorporation into fibrils and matrix. These studies utilized a triplet duplication in COL1A1 exon 44 that occurred in the cDNA and gDNA of two siblings with lethal OI. The normal allele encodes three identical Gly-Ala-Hyp triplets at aa 868-876, whereas the mutant allele encodes four. The register shift delays helix formation, causing overmodification. Differential scanning calorimetry yielded a decrease in T(m) of 2 degrees C for helices with one mutant chain and a 6 degrees C decrease in helices with two mutant chains. An in vitro binary co-processing assay of N-proteinase cleavage demonstrated that procollagen with the triplet duplication has slower N-propeptide cleavage than in normal controls or procollagen with proalpha1(I) G832S, G898S, or G997S substitutions, showing that the register shift persists through the entire helix. The register shift disrupts incorporation of mutant collagen into fibrils and matrix. Proband fibrils formed inefficiently in vitro and contained only normal helices and helices with a single mutant chain. Helices with two mutant chains and a significant portion of helices with one mutant chain did not form fibrils. In matrix deposited by proband fibroblasts, mutant chains were abundant in the immaturely cross-linked fraction but constituted a minor fraction of maturely cross-linked chains. The profound effects of shifting the collagen triplet register on chain interactions in the helix and on fibril formation correlate with the severe clinical consequences.

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