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In Depth Tutorials and Information
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Glycine
substitutions
NL
L
NL
L
Ala
NL
L
Ser
NL
L
Cys
NL
L
Val
NL
L
Arg
NL
L
Asp
NL
L
Glu
NL
L
Trp
FIGURE 10.2
Helical region glycine substitutions along the α2(I) collagen chain. The top line indicates amino acid positions in the triple-
helical region using the “legacy” numbering scheme. The first data row summarizes all glycine substitutions caused by single-base substitu-
tions. The rows below present the data for each substituting amino acid, indicated to the right end of each line. The vertical bars above and
below the lines indicate the substitutions. NL: non-lethal; L: lethal.
the non-lethal substitutions Gly334Ser (OI type IV
21
),
Gly337Asp (OI type III
/
IV
21
; OI type IV
21
) and Gly352Arg
(OI type I
/
IV; Nesbitt, personal communication). Even
small region 5 which runs from positions 694 to 706 is
interrupted by two non-lethal substitutions: Gly700Ala
(OI type I; Roughley, personal communication), and
Gly703Arg (OI type III
21
; OI type III
/
IV
29
).
In addition, there are now seven lethal substitu-
tions identified in the region 193 to 307
18,21,30
(Nesbitt,
personal communication; Lund, personal communica-
tion) prior to the start of region 1 which begins at posi-
tion 319. The gap between regions 1 and 2 (367 to 448)
has two more-recently published lethal substitutions at
positions 367 and 463
18
in addition to the three which
were noted when the regional model was first proposed.
The left boundary of region 3 needs to be adjusted to
accommodate lethal Gly to Asp substitutions at posi-
tions 535
31
and 544 (Nesbitt, personal communication).
Similarly, region 4 needs to be adjusted to accom-
modate a lethal Gly to Val substitution at position 619
(Nesbitt, personal communication). The gap between
regions 4 and 5 is now known to harbor four lethal sub-
stitutions: Gly649Glu (Symoens, personal communica-
tion), Gly655Glu,
30
Gly658Val
18
and Gly682Val (Lund,
personal communication). Finally, the left boundary
of region 8 needs to move leftwards to accommodate
the lethal Gly934Arg substitution
30
and rightwards to
accommodate the lethal substitutions Gly997Asp,
30
Gly1000Val (Symoens, personal communication) and
Gly1003Asp (Nesbitt, personal communication).
Historically, there have been several attempts to cor-
relate amino acid substitutions with the severity of OI
phenotype. Since the collagen triple-helix forms from the
C-terminus towards the N-terminus, amino acid substitu-
tions closer to the start of triple-helix formation will lead
to greater overmodification of collagen molecules which
is a classic feature of OI. In spite of early attempts to
establish genotype
/
phenotype models which suggested
otherwise,
23-25
current data show that the severity of the
phenotype is not linear along the α1-chain and there is lit-
tle evidence for any clustering of lethal variants. The only
significant clusters are ten consecutive exclusively lethal
substitutions between positions 703 and 772 and a fur-
ther seven between 910 and 946 of the α1-chain which lie
within two of the three ligand-binding hot-spot regions
in type I collagen.
26
The first cluster lies with ligand-bind-
ing region 2 and the region of lethal variants (703-772)
corresponds most plausibly to part of the binding site for
cartilage oligomeric matrix protein (COMP).
27
The sec-
ond lies within ligand-binding region 3 and the region of
lethal variants (910-946) has a partial overlap most plau-
sibly with a decorin core protein-binding site.
28
The regional model for lethal amino acid substitutions
has been much more fully developed for the α2-chain
than for the α1-chain, with eight clusters having been
identified.21
21
Even at the time of publication, these regions
were not populated exclusively with lethal substitutions
and there has been much in-filling of the regions with
non-lethal substitutions since (
Figure 10.2
). For example,
region 1 which runs from positions 319 to 364 harbors
