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CHAPTER
10
Osteogenesis Imperfecta Genotypes and
Genotyp
e-Phenotype Rela
tionships
Raymond Dalgleish
University of Leicester, Leicester, UK
INTRODUCTION
facilitate normal folding of the three α-chains into a tri-
ple helix. For the α1- and α2-chains of type I collagen, the
1014 amino acid sequence of the triple-helical region can
be presented as (Gly-Xaa-Yaa)
338
where the amino acids
in the Xaa and Yaa positions are commonly proline and
4-hydroxyproline, respectively. The DNA sequence motif
underlying the protein-repeat motif is GGNNNNNNN,
and sequence variation at either of the two G bases will
result in substitution of glycine (GGN) with another
amino acid. As all known substitutions affecting gly-
cine codons are confined to one or other of these bases,
the eight possible new amino acids are alanine, arginine,
aspartic acid, cysteine, glutamic acid, serine, tryptophan
and valine. The frequencies of each of the triple-helical
region glycine codons and the consequences of variants
arising in them are summarized in
Table 10.1
. The impli-
cations will be discussed in detail later in the section
dealing with amino acid substitutions.
There are four other key types of sequence variation
affecting collagen type I genes. Whole-gene deletions
result in complete loss of expression from the deleted
allele. Sequence variation at the junctions between exons
and introns results either in exon skipping or in “slippage”
of the junction such that the mRNA translational reading
frame is altered, resulting in nonsense-mediated decay
2
(NMD) of the mRNA. Small insertions and deletions (or
combinations of the two: “indels”) can result in the read-
ing frame either being maintained or disrupted depend-
ing on their length. Out-of-frame events normally result in
NMD, whereas in-frame events are varied in their conse-
quences. Finally, some sequence variants will result in the
creation of premature termination codons (PTCs) which
will normally lead to NMD of the mRNA. All of these
mechanisms will be discussed below in greater detail.
The principal cause of osteogenesis imperfecta (OI)
is sequence variation in the genes encoding the α1- and
α2-chains of type I collagen,
COL1A1
and
COL1A2
, respec-
tively. These variants are mostly dominant and many arise
de novo
, rather than being inherited from one or other par-
ent. Less commonly, OI also results from sequence vari-
ants in genes whose products assist with the modification
of collagen chains or act as chaperones for the selection,
folding or stabilization of chains. The focus of this chapter
will be on the mutations in
COL1A1
and
COL1A2
which
directly affect the α1- and α2-chains of type I collagen.
These individual α-chains are synthesized with a sig-
nal peptide and with N- and C-propeptides flanking the
long uninterrupted triple-helical domain. There are sev-
eral OI-causing sequence variants which interfere with
the function of the signal peptide of the α1-chain, but
none for the α2-chain. The function of the N-propeptides
of both chains is also compromised by sequence variants
with fewer in the α1-chain than in the α2-chain. Sequence
variants which eliminate the N-propeptide cleavage
site in either chain result in the arthrochalasis type of
Ehlers-Danlos syndrome
1
rather than OI. Consequently,
these variants will not be discussed further. In contrast,
sequence variants affecting cleavage of the C-propeptide
result in a high bone density variant of OI. The telopep-
tides which immediately lank the triple-helical regions
of each mature α-chain are also known to harbor disease
causing sequence variants. These classes of OI-causing
variants will be discussed later in more detail.
The triple-helical domains of collagen α-chains are
exquisitely sensitive to mutation because of the absolute
requirement for a glycine at every third amino acid to
