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100
200
300
400
500
600
700
800
900
1000
NL
L
Glycine
substitutions
NL
L
Ala
NL
L
Ser
NL
L
Cys
NL
L
Val
NL
L
Arg
NL
L
Asp
NL
L
Glu
FIGURE 10.1
Helical region glycine substitutions along the α1(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.
of which four are published,
15
and in each instance the
deletion results in OI type I which is consistent with the
notion of haploinsufficiency. A much larger deletion of
the chromosomal region chr17q21.33_q23.1del encom-
passing
COL1A1
has been demonstrated
16
using
in situ
fluorescence hybridization (FISH) but the identity of the
non-hybridizing probes is not reported. Although the
patient is described as have OI type I, the phenotype also
includes micrognathia and cleft palate (Robin sequence),
Marfanoid features, blue sclerae and a fracture at birth
with osteopenia on X-rays. In addition, there are sev-
eral patients harboring large “multi-exon deletions” of
COL1A1
resulting in a true OI phenotype. These include
deletions of exons 2 to 38 in a patient with OI type I,
exons 7 to 42 resulting in OI type IV, and 11 to 20 result-
ing in OI type I, all unpublished.
Similarly large deletions encompassing exons 23 to
25
8,17
and 39 to 48
18
result in OI type II. In
COL1A2
multi-
exon deletions for exons 1 to 18 (OI type IV: unpub-
lished), 7 to 11 (OI I
19
), 10 to 17 (OI
19
) and 34 to 40 (OI II
20
)
have been described. No complete deletions have been
described for
COL1A2
. Based on additional lines of evi-
dence, it is possible that the entire deletion of
COL1A2
would not result in haploinsufficiency and any apparent
OI phenotype, perhaps explaining why such deletions
have not been ascertained.
in
Figures 10.1 and 10.2
. The legacy amino acid number-
ing scheme is used in these figures and in discussions of
amino acid position throughout this section. Amino acid
substitutions are the most common cause of OI with all
possible replacing amino acids having been observed
apart from tryptophan in
COL1A1
. As has been noted
previously,
21
the observed proportions of each substi-
tuting amino acid do not correspond with theoretical
expectations. For
COL1A1
and
COL1A2
the proportion
of missense mutations which are lethal is 38.6 and 24.4%,
respectively, with all cases described as OI type II
/
III
being considered to be lethal. Of the 391 unique missense
mutations in
COL1A1
, 151 are lethal (38.6%) and the cor-
responding values for
COL1A2
are 352 and 86 (24.4%).
Substitutions towards the N-terminus of both α-chains
are likely to be non-lethal with no lethal substitutions
being encountered before helical region position 76 in
the α1-chain and 193 in the α2-chain. A subset of the
non-lethal substitutions in the early part of the α1-chain
results in a phenotype combining features of both OI and
Ehlers-Danlos syndrome (EDS).
22
Substitutions by valine,
arginine and aspartic acid are more likely to result in a
lethal phenotype in
COL1A1
than in
COL1A2
. There are
relatively few regions which are bereft of glycine sub-
stitutions in either type I collagen chain. Even with the
publication of more recent data, the longest such gap pre-
viously identified in the α2-chain is now 52 to 73 (eight
consecutive glycines) rather than the ten glycines noted
previously,
21
making the largest gap region 130 to 154
(eight consecutive glycines). Interestingly, the 52 to 73 gap
in the α2-chain aligns with a corresponding gap of seven
glycines at positions 49 to 67 in the α1-chain suggesting
that this region may not be functionally important.
HELICAL-REGION AMINO ACID
SUBSTITUTIONS
The distribution of amino acid substitutions along the
triple-helical regions of the α1- and α2-chains is presented
