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type I procollagen molecules are functionally “null”
and are consequently associated with a relatively mild
phenotype. These include mutations that result in a pre-
mature termination codon (nonsense, frameshift muta-
tions) leading to NMD or, if the mRNA is stable, rapid
degradation of the mutant polypeptide chain, without
incorporation into procollagen trimers.
60
Pro-α1(I) C-propeptide mutations (mostly missense
and frameshift mutations) that alter the structure of
the C-propeptide, thereby interfering with intra- and/
or interchain disulfide bond formation, usually result
in very severe or lethal forms of OI. They disturb pro-
collagen assembly, but do not completely prevent it,
and thereby allow incorporation of both wild-type and
mutant chains in the procollagen trimers. This results in
delay in helix folding and longer exposure of the pro-α
chains to post-translational modification, which can be
observed on biochemical analysis.
17,45,57,70,71
Pro-α1(I)
C-propeptide missense mutations vary in their pheno-
typic outcome, with phenotypes ranging from OI type I
to OI type II (
Table 13.1
), the majority of them being
either mild or lethal. Very recently, the crystal structure
of the C-propeptide domain of human type III procol-
lagen was reported, and known missense mutation in
the C-propeptides of fibrillar procollagens types I, II, III
and V were mapped onto the structure of the pro-α1(III)
C-propeptide. In most cases, the residue that is mutated in
the other procollagen types is conserved in the pro-α1(III)
C-propeptide. This conservation, as well as the strong sim-
ilarity of the structure of the pro-α1(III) C-propeptide and
that predicted for the other procollagen types, permitted
mapping of these mutations onto the procollagen type III
C-propeptide structure. From this map, it is clear that
mutations leading to mild or moderate OI phenotypes
generally involve surface-located residues in regions not
participating in interchain interactions, and these muta-
tions are therefore unlikely to interfere with folding or
trimerization. On the other hand, missense mutations in
COL1A1
associated with the most severe phenotypes are
clustered in three regions of the molecule: (1) mutations
near the C-terminus, which are involved in intrachain
disulfide bonding (Cys 5 - Cys8), interchain interaction
(Leu245, Arg137) and stabilization of the hydrophobic
core (Leu 218); (2) mutations near the region of the Cys
6 - Cys 7, disrupting intrachain disulfide bonding or inter-
nal hydrophobic interactions; and (3) mutations that inter-
fere with the (Cys1 - Cys4) intrachain disulfide bond and
the Ca2+-binding loop
8
(numbering corresponds to the
C-propeptides of the pro-α1(III) chain, starting from the
BMP1-cleavage site; see also
Figures 13.2 and 13.3
).
175
104
168
218
137
245
C
227
169
222
63
243
197
149
Ca
2+
229
194
206
59
41
81
38
148
Cys47-Cys64
(Interchain S-S)
37
44
94
92
56
Cys41-Cys73
Cys151-Cys196
Cys81-Cys243
52
FIGURE 13.2
Positions of known missense mutations in the C-propeptides of fibrillar procollagens I, II, III and V, mapped onto the structure of
the pro-α1(III) C-propeptide. One chain of the pro-α1(III) C-propeptide trimer is shown in wheat, with the other chains shown (in part) in light gray.
Numbering starts from the BMP1 cleavage site, according to the corresponding positions in the procollagen type III C-propeptide. Only mutation sites
where the corresponding residues in the pro-α1(III) chains are identical are shown. Sites associated with lethal or severe forms of OI or skeletal dyspla-
sias are in red and dark red, respectively, and those associated with mild or moderate forms in blue (OI) and dark blue (skeletal dysplasias). Asp222 is
in purple, as two different mutations at the corresponding residue in pro-α1(I) lead either to mild [p.(Asp1441His)]
68
or lethal [p.(Asp1441Tyr)]
57
OI.
Mutation sites in pro-α1(III) and pro-α1(V) are in green and dark green, respectively. Sites are numbered from the start of the C-propeptide domain.
(Drawn by using PyMOL, Version 1.4.1, Schrödinger, LLC; reprinted from
8
,
with permission.)
