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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
Author(s) -
Pace James M.,
Atkinson Mary,
Willing Marcia C.,
Wallis Gillian,
Byers Peter H.
Publication year - 2001
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.1193
Subject(s) - triple helix , collagen helix , biology , amino acid , osteogenesis imperfecta , procollagen peptidase , helix (gastropod) , type i collagen , extracellular matrix , genetics , microbiology and biotechnology , anatomy , ecology , snail , endocrinology
Triple helix formation is a prerequisite for the passage of type I procollagen from the endoplasmic reticulum and secretion from the cell to form extracellular fibrils that will support mineral deposition in bone. Analysis of cDNA from 11 unrelated individuals with osteogenesis imperfecta (OI) revealed the presence of 11 novel, short in‐frame deletions or duplications of three, nine, or 18 nucleotides in the helical coding regions of the COL1A1 and COL1A2 collagen genes. Triple helix formation was impaired, type I collagen α chains were post‐translationally overmodified, and extracellular secretion was markedly reduced. With one exception, the obligate Gly‐Xaa‐Yaa repeat pattern of amino acids in the helical domains was not altered, but 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 identity of these amino acids, in addition to third position glycines, is important 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. © 2001 Wiley‐Liss, Inc.