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CHAPTER
11
Structural Consequences of Glycine
Missense Mutations in Osteogenesis
Imperfecta
Barbara Brodsky
1
and Anton Persikov
2
1
Tufts University, Medford, MA, USA,
2
Princeton University, Princeton, NJ, USA
INTRODUCTION
of collagen folding and processing, molecular and fibril
structure, and mechanical and signaling function. How
does replacement of a Gly by a larger residue affect
the triple-helix conformation and stability? Should
replacement by a larger residue such as Val result in a
greater perturbation than a smaller residue such as Ser,
and will greater structural perturbation translate into
a more severe clinical phenotype? How does the loca-
tion of the mutation with respect to triple-helix ini-
tiation and specific binding sites affect severity? Is the
immediate sequence environment of a mutation site
an important factor? When early studies showed that
OI collagens with Gly missense mutations had excess
post-translational modification, the nature of the fold-
ing process and the consequences of misfolding came
into focus. As researchers have tried to understand why
a Gly replacement in type I collagen leads to a bone dis-
ease, it has proved necessary to probe all stages in the
multi-level assembly of the extracellular matrix result-
ing in mineralized collagen fibrils integrated into a
larger matrix. Our current understanding of the effect
of missense mutations will be reviewed here, consider-
ing the experimental studies and computational analy-
ses and their relation to the extensive OI database.
As described in other chapters in this volume, osteo-
genesis imperfecta (OI) is a collagen disorder which leads
to fragile bones, and encompasses a wide range of clini-
cal phenotypes. Type I collagen, the predominant pro-
tein in bone, serves as a matrix for mineralization, and
mutations in either the α1 or α2 chains of type I collagen
have been shown to cause the dominant form of OI (for
reviews see
1,2
). Although splicing errors, deletions, inser-
tions, and frameshift mutations have all been reported to
cause dominant OI, this chapter is focused on missense
mutations in type I collagen which lead to replacement of
a Gly within the repeating (Gly-Xaa-Yaa)
n
sequence. Such
Gly missense mutations represent the largest class of
dominant OI mutations. When these mutations were first
observed, there was a sense of the obvious: Gly residues
are required as every third residue to form the triple-helix
structure, so it is not surprising that replacing a Gly by
a larger residue would lead to a problem. OI appeared
to be a classic case, similar to sickle cell disease, where
alterations in protein structure due to a single amino acid
change brings pathology. But the sequence of events that
leads from a Gly missense mutation in collagen to the fra-
gility of bones has not been easy to untangle. The source
of the clinical heterogeneity seen for different OI cases
is perplexing. A Gly→Ser missense mutation at one site
in the triple helix may lead to a lethal phenotype in one
case, while in another case, a nearby Gly→Ser mutation
may lead to mild or moderate OI.
Attempts to track the sequence of events set off by a
missense mutation have forced a deeper consideration
OVERVIEW OF OI GLY MISSENSE
MUTATIONS
Most cases of OI are autosomal dominant and are
caused by mutations in one of the type I collagen genes:
COL1A1
or
COL1A2
(see Chapter 10). A landmark event
