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CHAPTER
18
OSX/SP7
Mutations and Osteogenesis
Imperfecta
José Antonio Caparrós-Martín
1,3
, Mona Aglan
4
, Samia Temtamy
4
,
Víctor Martínez-Glez
1,2
, María Valencia
1,3
, Jair Tenorio
1,2
, Pablo
Lapunzina
1,2
and Víctor Ruiz Pérez
1,3
1
CIBERER, Instituto de Salud Carlos III (ISCIII), Madrid, Spain,
2
Instituto de Genética Médica y
Molecular, Hospital Universitario La Paz-IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain,
3
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad
Autónoma de Madrid, Madrid, Spain,
4
National Research Centre, Cairo, Egypt
INTRODUCTION
patterning information to the mesenchyme in order
to generate primordia of individual skeletal elements.
These signals outline the three-dimensional coordinates
that determine the shape of mesenchymal condensa-
tions.
10
Among the molecules that pattern skeletal ele-
ments are secreted polypeptides of the Hedgehog, Wnt
and FGF families, and the TGF-superfamily, as well
as transcription factors of the Pax, Hox, homeodo-
main-containing, bHLH and Forkhead families.
11-13
In
membranous skeletal elements, cells in condensations
differentiate into osteoblasts, whereas in endochondral
skeletal elements, cells in condensations differentiate first
into chondrocytes to form the cartilage templates that
will later be replaced by bones. Chondrocytes deposit a
cartilage-specific extracellular matrix, proliferate and,
finally, hypertrophy and die. At the same time, some of
the mesenchymal cells surrounding cartilage invade,
together with blood vessels and osteoclasts, zones of
hypertrophic chondrocytes, differentiate into osteo-
blasts, and deposit a bone-specific matrix, replacing the
degraded cartilage matrix.
10
Differentiation of osteo-
blasts in membranous skeletal elements begins concur-
rently with that in the endochondral skeleton, suggesting
a temporal control synchronizing both modes of bone
formation. Members of the Sox family control the fate
of the chondrocyte lineage.
14,15
The transcription factor
Runx2/Cbfa1, a runt family polypeptide, has previously
been shown to be required for osteoblast differentiation.
AR-OI is due to a large number of genes.
1-8
In 2010
we reported the genetic analysis of a pedigree that has
led us to the identification of a new gene mutated in
AR-OI named
Osterix/SP7
.
9
The clinical findings from this
patient include recurrent fractures, mild bone deformities,
delayed tooth eruption, normal hearing and white sclera.
Using a combination of homozygosity mapping and can-
didate gene approach, we identified a homozygous single
basepair deletion in the
SP7/OSX
gene in an 8-year-old
Egyptian boy with OI and normal sclerae. This form of
OI has been designated OI type XII (OI12; MIM 613849).
9
Since all the previously known genes associated with
AR-OI (
CRTAP
,
LEPRE1
,
PPIB
,
SERPINHI
and
FKBP10
)
were either involved in the synthesis or post-translational
modifications of collagen type I directly, this finding rep-
resented a new view into the molecular basis of OI, since
SP7
encodes a transcription factor that is necessary for
osteoblast differentiation.
THE PROCESS OF OSTEOBLAST
DIFFERENTIATION AND ITS RELATION
WITH OSTERIX
The development of vertebrate endoskeletons is
initially controlled by molecular signals that provide
