what-when-how
In Depth Tutorials and Information
lamellar” appearance on polarized light examina-
tion. These patients form a distinct subgroup previ-
ously designated OI type VI. Autozygosity mapping of
the mutant gene in a Turkish family with moderately
severe OI identified a mutation in the FKBP10 gene, a
molecular chaperone coding for a FK506-binding pro-
tein which has peptidyl-prolyl isomerase activity.
54
This
discovery prompted investigation of similar inbred
families resulting in the identification of other chaper-
ones such as Serpin F1
55
and the molecular character-
ization of the peptidyl-prolyl isomerase B involved in
P3-hydroxylation.
56
or in the region of the BMPI cleavage site in COL1A1
result in distinct phenotypic effects which may show
high or low bone mass.
61,62
WHOLE GENE DELETIONS
Heterozygous complete COL1A1 deletions result
in very mild or no phenotypes.
63
Type I procollagens
are major organizers in the developing fetal brain and
thus mutations which markedly reduce gene expression
such as perinatally lethal forms are characterized by an
extremely severe brittle bone phenotype with increased
frequency of neuronal migration defects and frontal
lobe deficiency.64
64
DE
FECTS IN MINERALIZATI
ON
A further disorder with moderately severe OI with
autosomal recessive inheritance has been shown to
result from mutations in Osterix (OSX) which encodes
an osteoblast-specific transcription factor SP7/OSX
which belongs to the specificity protein (Sp) subgroup
of the Kruppel-like family of transcription factors.
57
In
mice Osx is essential in regulating the differentiation of
preosteoblasts to osteoblasts and operates downstream
from Runx2. It is important to note that mutations in
the reading frame of RUNX2 in humans result in cleido-
cranial dysplasia but mutations in the RUNX2 promoter
may result in osteoporosis alone.
OI with calcification of interosseous membranes plus
a predisposition of hyperplastic callus has recently been
shown to result from a single heterozygous mutation
in the 5′ untranslated region of IFITM5 which codes
for a 132 amino acid protein member of the interferon-
induced transmembrane gene family.
58,59
The common
mutation which has been found in all affected individ-
uals to date is a C > T transition in the 5′ UTR result-
ing in a new initiation codon which translates a protein
incorporating five additional amino acids. Furthermore
the protein which is also known as “bone restricted
ifitm-like protein” (BRIL) localizes to the osteoblasts of
osseous tissues but not at the zone of proliferating carti-
lage tissue. Its complete role in ossification is still to be
elucidated.
59
Mutations in the carboxy terminal peptidase of type
I collagen bone morphogenetic protein I were recently
shown to result in a brittle bone disorder with pheno-
typic and radiographic features which suggested OI of
moderate severity but with a high bone mass pheno-
type. Radiographically the features have no similarity
to the osteopetrotic or craniotubular remodeling dis-
orders. The p.Gly12Arg mutation in the signal peptide
region of BMPI detected in this Turkish kindred inter-
feres with post-translational N-glycosylation of the pro-
tein and its secretion from the endoplasmic reticulum.
60
Several further studies confirm that mutations in BMPI
PATIENT AND PARENT SUPPORT
ORGANIZATIONS AND THE
FACI
LITATION OF RESEARCH I
N OI
Concerned parents, their families and health profes-
sionals in North America formed the OI Foundation
Inc. in 1970 with a broad remit to provide family sup-
port, educational resources, sponsor conferences
and advocacy for people with OI. In Europe the OI
Federation of Europe (OIFE) was formed in 1993 to
provide an umbrella committee of delegates and an
executive to represent all the associations and affiliates
associations including OI Australia. Some of the charter
associations forming OIFE go back much further and
were formed at a time that the first parent and patient
support groups were forming.
Finally there is some overlap with organizations
set up to fund raise for research, such as the Shriner's
Foundation for Children and Children's Brittle Bone
Foundation, which have provided major and sus-
tained support for basic and applied research. Through
enhancing awareness of OI in communities and sup-
porting development of centers of expertise for clini-
cal management of OI, coordinated investigation and
research, these organizations can take much of the
credit for fostering the advances made in OI care and
research.
REVI
EWS AND DOCTORAL TH
ESES
In this overview of the history of advances in clini-
cal care and research, there is no space to do justice to
all the previous reviews. However, mention should
be made of the classic work, the
Brittle Bone Syndrome
published in 1983, which was already in an advanced
stage of completion at a time when major advances in
the clinical, genetic, protein biochemical and molecular
