what-when-how
In Depth Tutorials and Information
Impaired splicing at the N-terminal cleavage site leads
to retention of the N-propeptide causing defective col-
lagen crosslinking. The associated phenotypes are
Ehlers-Danlos syndrome (EDS) types VIIA, due to α1(I)
involvement, and VIIB due to involvement of the pro-
α2(I) chain.
30
As reported by Byers et al., some individuals
with EDS VII suffer fractures, perhaps as a consequence
of defective mineral deposition secondary to the incorpo-
ration of collagen fibrils containing the N-propeptide.
30
ADAMTS-2 is a procollagen N-proteinase, and the muta-
tions of its gene are responsible for human Ehlers-Danlos
syndrome type VIIC and bovine dermatosparaxis.
31
The majority of reported C-propeptide mutations
affect the pro-alpha-1(I) chains. Substitutions altering
COL1-alpha-1(I) C-propeptide processing result in mild
OI with increases in vertebral DXA Z-scores and increases
in histomorphometric tissue mineralization that are coun-
terintuitive for OI, due to accelerated mineralization.
28
Cabral et al. have identified seven children with type
III or IV OI who exhibited severe large and small joint
laxity and early progressive scoliosis.
32
Termed “OI/
EDS,” mutations were identified in the first 90 residues
of the helical region of alpha-1(I) collagen. These muta-
tions delayed or prevented removal of the procollagen
N-propeptide by ADAMTS-2. The mutated pN colla-
gen is incorporated into extracellular matrix by cultured
fibroblasts and osteoblasts and as noted above by Byers,
is associated with altered matrix mineralization.
The C-terminal domain directs assembly of the type I
heterotrimer. Collagen type I pro-alpha-1(I) and pro-
alpha-2(I) chains assemble from the C- to the N-terminal
direction. Chain assembly is stabilized by intrachain
disulfide bonds. Removal of the C-propeptide is accom-
plished by several tolloid-like proteinases, includ-
ing bone morphogenic protein 1 (BMP1), which is the
major C-terminal proteinase.
33-35
BMP1/tolloid-like
(Drosophila) proteinases are major enzymes involved in
extracellular matrix assembly and in the activation of sev-
eral bioactive molecules within the TGF-beta superfamily
of proteins (see Chapter 22). BMP1 mutations resulting in
an OI phenotype are discussed in Chapter 19.
36
The ini-
tial reports of BMP1 mutation involved an Egyptian fam-
ily with two children diagnosed with severe autosomal
recessive OI and a large umbilical hernia.
The structure of the pro-alpha-2(I) C-propeptide is
essential to orderly procollagen trimer assembly. Pace
et al.
37
reported four adult patients with clinical features
of mild OI type IV, but exhibiting marked clinical vari-
ability in both scleral color and fracture incidence. These
patients expressed dominant mutations (three missense
substitutions, and one insertion leading to a frameshift) in
the
COL1A2
gene that altered sequences of the pro-alpha-
2(I) C-propeptide and impaired disulfide bonding.
In vitro
fibroblast cell cultures demonstrated that the assembly of
pro-alpha-2(I) chains was altered so that two species of
type I procollagen were observed: the major component
contained two pro-alpha-1 and one pro-alpha-2 chains,
while the minor component contained three pro-alpha-
1(I) chains (homotrimer). Two of these patient's cells
secreted significant amounts of homotrimer. The total col-
lagen synthesis was decreased in these cells.
The synthesis of pro-alpha-1(I) homotrimer due to
failure of pro-alpha-2(I) chain incorporation has been
reported in three situations: in the
oim/oim
mouse,
38
in
a beagle puppy with fractures consistent with type III
OI
39
and, in contrast to the above milder cases, in sev-
eral humans with moderately severe OI. Nichols et al.
reported on a boy presenting Sillence type III OI. The
main biochemical defect was the synthesis of an abnor-
mal pro-alpha-2(I) chain which did not associate with
pro-alpha-1(I) chains permitting only pro-alpha-1(I)
homotrimer to be formed.
40
de Vries and deWet reported
a patient with moderately severe OI who synthesized
three kinds of type I homotrimers: a normal type I tri-
mer, a type I trimer with one mutant pro-alpha-1(I) chain
and two normal chains, and a type I trimer with two
mutant pro-alpha-1(I) chains and one normal pro-alpha-
2(I) chain.
40,41
Pihlajaniemi reported a severely affected
patient with an autosomal recessive form of OI in which
the patient has inherited two abnormal pro-alpha-2(I)
collagen alleles from consanguineous parents resulting in
the secretion of only pro-alpha-1(I) homotrimers.
6
In earlier reports, OI was characterized showing “phe-
notypic and clinical heterogeneity.” That description
remains to this day: the clinical assessment of OI patients,
children to adults, continues to uncover highly variable
phenotypes with regard to physical findings and fracture
rates even within the same kindred. The genetic hetero-
geneity is discussed above and in individual chapters in
this topic. This variability is also seen in the response of
individual patients to treatment with bisphosphonates:
although pamidronate treatment is reported to decrease
fracture rates in children by approximately 50%, certain
children do not, for unexplained reasons, decrease their
fracture rate after prolonged periods of treatment. This
quandary represents but one of the issues, epidemiological,
clinical and genetic, awaiting solution for patients with OI.
EPIDEMIOLOGY OF OI
All the epidemiological studies of OI predate the
recent identification of the modern forms of recessively
inherited forms of OI. It is reassuring, however, that
almost anyone with OI, even the recessive forms, would
have been thought to have OI and so classified for any
of the population surveys completed. As noted above,
almost all the individuals with mutations in the new
genes would have been included in the Sillence classifi-
cation as having OI type II, OI type III or OI type IV. The
