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AMINO ACID DELETIONS AND
DUPLICATIONS
TABLE 10.6
dnA sequence Alterations in
COL1A1
and
COL1A2
leading to OI
COL1A1
COL1A2
In addition to the sequence variants already dis-
cussed,
COL1A1
and
COL1A2
also harbor several small
insertions, deletions, duplications and insertion
/
dele-
tion (indel) variants. The consequences of these variants
depend upon their size and location, and those result-
ing in frameshifts have already been discussed. Small
insertions, deletions, duplications and indels result-
ing in in-frame alterations to the amino acid sequence
are relatively common in both genes, with 20 examples
in
COL1A1
and 15 in
COL1A2
. For
COL1A1
, apart from
the single-amino acid deletion p.(Val856del), all other
individuals have OI type II or OI type III phenotypes. In
comparison,
COL1A2
events lead to a larger proportion
of individuals with OI type IV.
Substitutions
1078
723
Deletions
178
36
Duplications
41
15
Insertion
/
deletions
11
5
Insertions
10
-
As more data have been added to the OI database,
the effect has largely been to confound attempts to delin-
eate clear genotype
/
phenotype relationships, rather than
to illuminate. It is probable that progress in this quest
will depend upon the establishment of a true OI knowl-
edgebase to supersede the existing variant-centric data-
base and the identification of genetic modifiers of the OI
phenotype.
IN
TRAFAMILIAL VARIABILI
TY
References
Variability of the phenotype between unrelated
individuals harboring the same sequence variant is
well documented. Intrafamilial variability is rather
less expected but there are several well-documented
accounts in the literature. The most extensively charac-
terized example is in 64 individuals from 22 Old Order
Amish sibships, for which a founder-effect can be dem-
onstrated, in which the
COL2A1
variant p.(Gly700Cys)
(Gly610Cys) segregates with a variable OI phenotype.
63
Although the phenotype was relatively severe in the
proband cluster, the overall data for this community
harboring the variant is that the phenotype ranges
from mild to moderate. Several other examples of intra-
familial variability can be explained by one of the par-
ents of an affected individual being somatically mosaic
for the variant harbored in their offspring.
30,64-66
It has
been suggested that the variability of the phenotype
caused by the p.(Gly700Cys) variant may be associated
with variation in the
PTGS2
gene on chromosome 1.
67
VARIANT SUMMARY
Base substitutions are, by far, the most common type
of sequence variation detected in
COL1A1
and
COL1A2
irrespective of the phenotypic outcome, accounting for
82% and 93% of all variants in these genes, and most
variants lie in the exons. Data for all variant types are
summarized in
Table 10.6
.
COL1A1
harbors variants in
all exons apart from exon 4, with exon 37 being the most
densely populated with variants in 60 unrelated individ-
uals. For
COL1A2
, where the variants are sparser, none
are found in exons 1, 2, 5 and 10, and the exon harboring
most is 19 with variants from 95 unrelated individuals.
[10]
[11]
[12]
[13]
[14]
