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TABLE 13.2
Positions and Consequences of Known mutations
in the C-Propeptides of the Pro-α2(i) Chain
Mutation (protein
level)
Mutation
Type
Exon
OI Type
Reference
41
b
49
p.(Ala1119Thr)
Missense
OI I + HBM
49
p.(Asp1120Ala)
Missense
OI + HBM
62
49
p.(Thr1148Pro)
Missense
OI°
61
49
p.(Cys1163Arg)
Missense
OI IV
63
49
p.(Asp1165Glu)
Missense
OI I
64
FIGURE 13.1
Biochemical collagen analysis of the secreted type I
and III collagen proteins. (A) An abnormal migration pattern for
type I collagen is observed for a patient (OI type IV) harboring the
p.(Ala1286Arg) mutation in exon 50 of the
COL1A1
gene. The muta-
tion causes severe overmodification of the α1(I) collagen chain, while
the α2(I) collagen chain migrates slightly higher through gel. (B) A
slightly decreased intensity for the type I collagen bands is detected for
a patient (OI type I) carrying the p.(Cys1299*) in exon 50 of the
COL1A1
gene. (C) For a patient (OI type I) harboring the p.(Pro1182Arg) in exon
50 of the
COL1A2
gene a near normal electrophoretic pattern for type I
collagen is observed. (D) A patient (OI type I), carrying the p.(Trp1347*)
mutation in exon 52 of the
COL1A2
gene shows a broadened band rep-
resenting the α1(I) chain; which is decreased in intensity. In addition,
the α2(I) band has an increased mobility, an observation that has been
documented in other
COL1A2
C-propeptide mutations.
63
50
p.(Gly1176Val)
Missense
OI IV
63
b
50
p.(Pro1182Arg)
Missense
OI I
42
50
p.(Cys1195Tyr)
Missense
OI I
50
p.(Glu1201*)#
Nonsense
EDS
65
a
51
p.(Asn1262Ser)
Missense
OI I
b
51
p.(Thr1269Pro)
Missense
OI I
51
p.(Leu1300Glnfs*13)
Frameshift
OI I
a
a
51
p.(Asp1315Argfs*5)
Frameshift
OI I
51
p.(Asp1315Val)
Missense
OI IV
63
51
p.(Ser1318Phefs*2)
Frameshift
OI IV
63
52
p.(Glu1323Glyfs*45)
Frameshift
OI I
66
was identified in two adult siblings with multiple long
bone fractures, scoliosis and tendon calcification upon
Achilles' tendon rupture and hearing loss. They also had
elevated DEXA BMD z-scores, and had normal teeth, no
blue sclerae and normal stature.
39
Finally, a pro-α2(I)_
p.(Asp1220Ala) was reported in a large family with
severe joint hyperlaxity, blue sclerae and elevated DEXA
BMD
z
-scores.
62
Interestingly, a homozygous mutation in the gene
encoding BMP1 has recently been identified in a family
with multiple fractures and increased bone mineral den-
sity, suggesting that impaired C-propeptide cleavage by
BMP1 (either by mutations in BMP1 or mutations affect-
ing the BMP1 cleavage site in
COL1A1
) can cause a dis-
tinct form of OI with high bone mass.
79
b
52
p.(Trp1324*)
Nonsense
OI I
b
52
p.(Lys1332Glu)
Missense
OI
52
p.(Asn1334Serfs*34)#
Frameshift
OI III
67
b
52
p.(Leu1347*)
Nonsense
OI I
a
52
p.(Gly1350Ser)
Missense
OI I
52
p.(Ile1360Val)
Missense
OI ?
a
52
p.(Phe1365Leu)
Missense
OI I
68
52
p.(*1367Glnext*5)
Stop codon
mutated
OI IV
69
Numbering starts from de methionine at the translation initiation site. HBM: high bone
mass.
#
homozygous mutation
°
This inherited variant was identified in the patient, in addition to the de novo
pathogenic p.(Leu1464Pro) substitution in
COL1A1
. It is not clear if this
COL1A2
variant modifies the patients' phenotype.
a
Unpublished, see
https://oi.gene.le.ac.uk
b
Personal observation of the authors.
GENOTYPE-PHENOTYPE
CORRELATIONS
controls and to other OI patients. Although steady-state
fibroblast collagen from both children showed mini-
mal electrophoretic abnormalities, processing of the
C-propeptide of type I procollagen was severely delayed,
as measured by pericellular and
in vitro
assays.
41
A few other patients with mutations affecting the
C-propeptide cleavage site have been identified (
Tables
13.1 and 13.2
). A pro-α1(I)_p.(Asp1219Glu) substitution
was identified in a large multi-generation family with
OI type I with normal dentition and normal hearing.
42
Furthermore, a pro-α1(I)_p.(Ala1218Thr) substitution
The severity of the OI phenotype resulting from
C-terminal propeptide mutations is dependent on the
type of chain involved (the pro-α1(I) or the pro-α2(I) col-
lagen chain) and the extent to which mutations compro-
mise the molecular assembly of procollagen molecules.
Pro-
α
1(I) C-Propeptide Mutations
Pro-α1(I) C-propeptide mutations that completely
prevent incorporation of mutant pro-α chains into the
