Deletions and duplications of Gly-Xaa-Yaa triplet repeats in the triple helical domains of type I collagen chains disrupt helix formation and result in several types of osteogenesis imperfecta

Triple helix formation is a prerequisite for the passage of type I procolla gen from the endoplasmic reticulum and secretion from the cell to form extr acellular fibrils that will support mineral deposition in bone. Analysis of cDNA from 11 unrelated individuals with osteogenesis imperfecta (OI) revea led the presence of 11 novel, short in-frame deletions or duplications of t hree, nine, or 18 nucleotides in the helical coding regions of the COL1A1 a nd COL1A2 collagen genes. Triple helix formation was impaired, type I colla gen alpha chains were post-translationally overmodified, and ex. tracellula r secretion was markedly reduced. With one exception, the obligate Gly-Xaa- Yaa repeat pattern of amino acids in the helical domains was not altered, b ut the Xaa- and Yaa position residues were out of register relative to the amino acid sequences of adjacent chains in the triple helix. Thus, the iden tity of these amino acids, in addition to third position glycines, is impor tant for normal helix formation. These findings expand the known repertoire of uncommon in-frame deletions and duplications in OI, and provide insight into normal collagen biosynthesis and collagen triple helix formation. Hum Mutat 18:319-326, 2001. (C) 2001 Wiley-Liss, Inc.