what-when-how
In Depth Tutorials and Information
FIGURE 18.3
Clinical and radiological findings in the patient with an
OSX
mutation. Note bowing of the upper and lower limbs.
Radiographs demonstrating femur fractures and photographs showing bowing of the long bones of the arms and leg.
(Adapted from
9
)
including
Collagen 1A1
,
Bone sialoprotein
and
Osteocalcin
.
10
In addition, these mice display bone-bending deformities
similar to those seen in patients with OI.
10
We screened the proband for the presence of
OSX
mutations by genomic amplification followed by direct
sequencing of the two
SP7
coding exons and at least
100 bp of the adjacent intronic sequences, and identified
a homozygous single nucleotide deletion, c.1052delA,
in the last exon of this gene (
Figure 18.4
). The frameshift
caused by this mutation introduces 18 novel residues at
codon 351 before running into a premature termination
codon (p.Glu351Glyfs*19). Segregation analysis of the
mutation within the family showed that both parents
homozygous SNPs and in doing so we found five large
regions of homozygosity in the patient that were not
shared by his normal sibling. These regions were on
chromosome 2 (two regions of 3.5 and 4 Mb), chromo-
some 4 (8.1 Mb), chromosome 11 (14.5 Mb) and chro-
mosome 12 (19.3 Mb). Evaluation of the transcripts
comprised in each region revealed the presence of a
candidate gene,
SP7/OSX
(MIM 606633), in the homo-
zygosity block of chromosome 12 (12q13.13). We consid-
ered
OSX
to be a good candidate for the disease because
of the null mice model. As commented earlier,
Osx
null mice are deficient in osteoblast differentiation and
have reduced expression of osteoblast-specific markers
