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TABLE 13.1
Positions and Consequences of Known mutations in the C-Propeptides of the Pro-α1(i) Chain
CP III
Equivalent
Exon
Mutation (protein level)
Mutation Type
OI Type
Ref.
a
51
p.(Asn1394Ser)
Missense
175 (Asn)
OI I
51
p.(Asp1413Asn)
Missense
194 (Asp)
OI II
42
46
52
51
p.(Ser1417Metfs*14)
Frameshift
OI II
46
51
p.(Thr1416Argfs*11)
Frameshift
OI IIC
53
b
52
p.(Trp1422*)
Nonsense
OI II/III
52
p.(Thr1431Ile)
Missense
OI IV
54
52
p.(Leu1437Gln)
Missense
218 (Leu)
OI II
55
b
52
p.(Ile1439Thr)
Missense
OI III/IV
52
p.(Asp1441His)
Missense
222 (Asp)
OI I
56
52
p.(Asp1441Tyr)
Missense
222 (Asp)
OI II + HBM
57
b
52
p.(Pro1444Leufs*95)
Frameshift
OI III
52
p.(Pro1444Aspfs*106)
Frameshift
OI I
58
52
p.(Val1447Argfs*104)
Frameshift
OI I
59
a
52
p.(Gly1448Asp)
Missense
229 (Gly)
OI I/IV
52
p.(Glu1453Argfs*96)
Frameshift
OI I
60
52
p.(Leu1464Pro)
Missense
245 (Leu)
OI III
61
Numbering starts from de methionine at the translation initiation site. Corresponding positions in the procollagen III C-propeptide (CPIII), numbered
from the BMP1 cleavage site, are included for the hitherto reported missense mutations
8
(see also
Figure 13.2
). HBM: high bone mass.
a
Unpublished, see
https://oi.gene.le.ac.uk
b
Personal observation of the authors.
mutation altering the last 30 amino acids of the pro-α2(I)
C-propeptide.
77
Intriguingly, a number of other homo-
zygous or compound heterozygous
COL1A2
null muta-
tions have been reported in humans, not resulting in OI,
but in an EDS-like phenotype (EDS, valvular type).
65,78
Those mutations were shown to result in NMD of unsta-
ble mutant mRNA and assembly of pro-α1 homotrimers.
Therefore, given that pro-α1 homotrimer formation alone
does not lead to OI, the intracellular accumulation of
mutant pro-α2(I) chains and the cellular alterations result-
ing from a high rate of destruction of these chains in the OI
patient are thought to contribute to the skeletal phenotype.
In 2008, Pace et al. reported four dominant mutations
in the
COL1A2
gene that alter the sequence of the pro-
α2(I) C-propeptide, including three missense mutations
that alter highly conserved amino acids [p.(Asp1315Val),
p.(Gly1176Val) and p.(Cys1163Arg)] and one frameshift
mutation [p.(Ser1318Phefs*2)] that deletes several highly
conserved amino acids. Cultured cells synthesized pro-
α2(I) collagen chains that were slow to assemble with
pro-α1(I) collagen chains to form heterotrimers that were
retained intracellularly. Furthermore the p.(Cys1163Arg)
and the p.(Ser1318Phefs*2) were shown to result in for-
mation of significant amounts of pro-α1(I) homotrimers.
63
These findings show that the C-propeptide of pro-α2(I),
like that of pro-α1(I), is essential for efficient assembly of
type I procollagen heterotrimers. When comparing the
phenotypic outcome of pro-α2(I) C-propeptide mutations
to that of mutations in the pro-α1(I) C-propeptide, these
mutations were all associated with a milder form of OI.
In
Table 13.2
an overview of all hitherto reported
COL1A2
affecting the pro-α2(I) C-propeptide and their associated
OI phenotype is given.
Mutations that Interfere with Cleavage of the
Procollagen Type I C-Propeptide
A special class of mutations involves those that lead to
a defect of the C-proteinase cleavage site. Lindahl et al.
reported two children with OI with substitutions in the
type I procollagen C-propeptide cleavage site, respec-
tively in the pro-α1(I) [p.(Asp1219Asn)] and the pro-α2(I)
[p.(Ala1119Thr)] collagen chain. Both children had mild
OI phenotypes with normal growth, light gray sclerae,
straight spines, normal dentition, hearing and cardiopul-
monary examinations. They did, however, present a dis-
tinctive high bone mass phenotype, with elevated DEXA
bone densitometry measurements when compared to
