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If anything, it is easier to define regions in the α2-chain
which are free of lethal substitutions. The region 661 to
679 harbors ten different non-lethal substitutions at seven
consecutive glycine positions. The region 712 to 751 har-
bors 14 different non-lethal substitutions at 11 glycine
positions. Finally, the region 712 to 751 harbors 7 different
non-lethal substitutions at 6 glycine positions.
The available data suggest that there is consider-
able inter-individual phenotypic variation for any given
amino acid substitution with the severity often ranging
from mild to severe. Twenty-nine individuals harbor the
COL1A1
p.(Gly257Arg) variant and their phenotypes
comprise 17 type I, 1 type III, 10 type IV and 1 type I
/
I V.
However, the 11 individuals harboring the
COL1A1
p.(Gly719Ser) variant all present with a type III OI phe-
notype.
COL1A2
reflects somewhat the same picture
with the 33 individuals harboring the p.(Gly328Ser) vari-
ant having phenotypes varying from mild to severe.
However, there are no instances of
COL1A2
substitution
variants harbored by substantial numbers of individu-
als (>10) where there is clear evidence for uniformity
of the phenotypic consequence. In fact, the
COL1A1
p.(Gly719Ser) variant appears to be unique in this respect.
Some patients with OI exhibit increased bone density
associated with alterations to the amino acid sequence
around the C-propeptide cleavage site. This has been
demonstrated for the
COL1A1
p.(Asp1219Asn) vari-
ant and the
COL1A2
p.(Ala1119Thr) variant
32
but there
is also limited supporting evidence in the published
accounts of nearby variants. In
COL1A1
, the unpublished
p.(Ala1218Thr) variant leads to “fracturing bone disease”
and increased bone density. The p.(Asp1219_Ala1221del)
deletion variant in the same gene results in OI type III,
but the published account makes no mention of bone
density with respect to the affected individual.
33
The
p.(Asp1219Glu) variant leads to OI type I but, again, the
published account does not mention bone density even
though the variant and its possible consequences are dis-
cussed at length.
16
In
COL1A2
the variant p.(Tyr1117Cys)
leads to OI type III but the published account does not
suggest that there is increased bone density in the pro-
band or in his elder siblings.
34
The p.(Asp1120Ala)
variant in the same gene is described as resulting in
increased bone density (unpublished).
TABLE 10.3
PTCs in
COL1A1
Resulting in non-Type I OI
DNA
Variant
Protein
Variant
Reported
Occurrences
Other OI
Types
c.757C>T
p.(Arg253*)
5
IV
c.1243C>T
p.(Arg415*)
8
III
/
IV, IV
c.1405C>T
p.(Arg469*)
2
IV
c.1789G>T
p.(Glu597*)
1
IV
c.2644C>T
p.(Arg822*)
7
IV
c.3806G>A
p.(Trp1269*)
2
IV
c.3824G>A
p.(Trp1275*)
1
IV
PTCs at seven positions in COL1A1 yield OI types which are inconsistent with the
expected OI type I phenotype.
null alleles of
COL1A1
or
COL1A2
by way of a number of
different mechanisms. The complete deletion of
COL1A1
has already been discussed as one such mechanism.
Translation initiation site sequence variants are a
recognized cause of human inherited disease
35
and
examples have been identified in
COL1A1
, though not
in
COL1A2
. The three variants (c.1A>G, c.2T>C and
c.3G>T) all result in mild forms of OI which are consis-
tent with haploinsufficiency for α1-chains.
Variants that generate PTCs also result in haploin-
sufficiency as a consequence of the mRNAs which har-
bor PTCs being degraded by NMD
2
which evolved as
a protective mechanism to ameliorate the effects of the
expression of truncated proteins. OI caused by PTCs
resulting from single-base substitutions is confined to
the
COL1A1
gene where 39 unique variants have been
recorded in total. Somewhat contrary to expectation, not
all of these variants result in type I OI (
Table 10.3
). For
example, the c.1243C>T variant in exon 19 which yields
the p.(Arg415*) PTC is reported to result in OI type IV in
one patient
36
and OI type III
/
IV in another.
37
In the latter
case, the patient phenotype has been confirmed directly
with the authors. The c.1405C>T variant in exon 21 yield-
ing the p.(Arg469*) PTC resulting in OI type IV
38
has
also been confirmed directly with the authors. Although
it has not been possible to directly confirm the OI type
for all non-type I patients, these findings suggest that
the genotype
/
phenotype relationship for PTCs cannot
be explained simply in terms of functionally null alleles.
However, phenotypes other than OI type I do lie mostly
toward the milder end of the OI spectrum of severity. The
only recorded PTC in
COL1A2
results not in OI but in a
recessively inherited form of EDS with cardiac valvular
disease.
39
This finding underlines the less important role
of α2-chains in the formation of functional type I collagen
and suggests that
COL1A2
PTCs may be generally reces-
sive and under-reported as a consequence.
Frameshifts as a consequence of small deletions, inser-
tions or insertion
/
deletion (indel) events are common in
START CODONS, PREMATURE
TERMINATION CODONS AND
FRAMESHIFTS
In OI type I the underlying genetic basis is commonly
distinctly different compared with the other OI types.
Typically, OI type I arises through the synthesis of an
insufficient amount of type I collagen. The causative vari-
ants result in haploinsufficiency14
14
by creating functionally
