what-when-how
In Depth Tutorials and Information
TABLE 1.2
Potentially Progressively Deforming OI with Normal
Sclerae (OI Type III)
collagen/matrix molecular interactions. An excellent
review of the collagens and the status of knowledge
about post-translational modifications was published
in 2004 suggesting that there might be other forms of
OI which resulted from mutations in post-translational
modifying enzymes and chaperone processes.
51
This
seems to have been largely ignored by the OI research
community. This is surprising in that the role of HSP47
(Colligin-1) and SerpinF1 (Colligin-2) as collagen chap-
erones and their potential importance in intracellu-
lar trafficking had been elucidated in 1992 and 1997,
respectively.
It was to the credit of Hans-Peter Bachinger and
colleagues at the Shriner's Hospital in Portland who,
in a carefully executed study of type I collagen bio-
chemistry, demonstrated the requirements for prolyl
3-hydroxylation of procollagen alpha chains.
24
Leprecan
(LEPRE1) is part of a complex with cartilage associated
protein (CRTAP) and cyclophilin B (CYPB) (also known
as peptidyl protein isomerase PIPB), which has pepti-
dyl-prolyl cis-trans isomerase activity. The complex is
essential for prolyl 3-hydroxylation, PIPB catalyzes the
rate limiting step of helix folding, and the complex is
also a potent molecular chaperone.
25
This multi-protein complex hydroxylates the proline
at codon 986 in procollagen α1(I) and at codon 707 in
procollagen α2(I) in the 3′ position. In the α1(I) chain,
the 3′-hydroxylation is very specific to α1(I) proline
986. All other hydroxyprolines are hydroxylated in the
4-position. Defects in 3-hydroxylation can be detected
in a variety of tissues by MSMS which detects the mass
shift due to loss of the oxygen atom at proline 986 in the
α
1
chain of type I collagen.
52
In the new international
nomenclature of OI 2010, six types of OI, three progres-
sively deforming and three perinatally lethal disorders,
result from disturbance of P3H1.
OMIM
Name
OMIM of
Condition
Disorder-Gene
Inheritance
OI type III-COLIA1
AD
AR
259420
OI type III-COLIA2
AD
AR
OI type III-CRTAP
VII
AR
610682
OI type III-P3H1/LEPRE1
VIII
AR
610915
OI type III-PPIPB
IX
AR
259440
OI type III-FKBP10
XI
AR
610968
OI type III-SERPINH1
X
AR
613848
OI type III-SP7/OSX
XII
AR
606633
OI Type III-SERPINF1
VI
AR
613982
OI Type III-BMP1
XIII
AR
112264
OI Type III-TMEM38B
XIV
AR
615066
OI Type III-WNT1
XV
AR
615220
The new nomenclature (2010) has attempted to
return to a descriptive grouping of syndromes. In
Table
1.1
, the descriptive grouping is compared with the for-
mer numerical nomenclature which will continue to be
used as a short-hand. One of the concerns expressed
from time to time is that the numerical nomenclature
(I-V) is confused with some type of severity scale. It
should be remembered that the numerical nomencla-
ture ordered the syndromes in terms of the order they
were described and nothing more.
What has been unexpected has been the considerable
heterogeneity in progressively deforming types of OI
and the large number of autosomal recessive disorders
which result in phenotypes with moderate to severe or
extremely severe bone fragility.
COLLAGEN AND MOLECULAR
CHAPERONES
A RETURN TO RESEARCH IN MATRIX
BIOLOGY
It had been known for some time that collagen poly-
peptide assembly and trafficking through the endoplas-
mic reticulum was a key aspect of collagen synthesis
and secretion and that mutant polypeptide chains were
abnormally processed.
53
The main focus had been on
the influence of procollagen helical mutations and their
disturbance of normal processes of 4-prolylhydroxyl-
ation and chaperones, particularly HSP47.
But the question remained: what of other chaper-
ones? Approximately 4% of children with a moderately
severe OI phenotype with normal scleral hue and nor-
mal teeth have a type of OI characterized by a distinc-
tive pattern on bone histomorphometry with excessive
osteoid on the trabecular margins and a “fish scale-like
During the 1990s the hype generated by rapid dis-
coveries of collagen mutations in both COLIA1 and
COLIA2, and the observation that specific classes of
collagen mutations resulted in and were characteristic
of the four phenotypes which had formed part of the
historical numerical nomenclature of OI syndromes,
obscured a large body of data which suggested that
there were other forms of OI and that these might be
significant particularly in specific (non-European) pop-
ulations.
8
Some researchers continued to pursue the
less glamorous and laborious task of understanding the
fundamental mechanisms of post-translational modi-
fication and trafficking of collagen proteins as well as
