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FIGURE 18.1
Protein effect of the c.1052delA mutation. The picture at the top shows the position of the three zinc-fingers represented by
blue rectangles in the normal (Wt) and mutant (Mut) SP7 proteins. The mutant protein is missing the third zinc-finger and the new residues
incorporated after the frameshift are indicated in red. The lower panel shows the sequence of amino acids corresponding to the DNA-binding
region of normal and mutant OSX. Conserved cysteine and histidine residues involved in zinc ion coordination corresponding to each one of
the individual zinc-finger are highlighted in different colors. The amino acids inserted after the mutation are in red. Numbering is related to the
reference sequence NP_690599.1.
(Adapted from
9
)
In agreement with the craniofacial features identified in
the patient we described,
9
both endochondral and intra-
membranous bone formation were found disrupted
in the
Osx
null mice. Since constitutive ablation of
Osx
is perinatal lethal, the function of Osx in adult bone
has been studied using conditional models.
Osx
null
embryos have a significant reduction of type I collagen
expression in their condensed mesenchyme of membra-
nous skeleton, as well in the periosteum. Postnatal inacti-
vation of Osx using tamoxifen inducible
Col1a1-CreERT2
mice resulted in impaired bone formation due to reduced
expression of osteoblast-specific markers leading to
increased fractures and osteopenia.
32
FIGURE 18.2
Pedigree of the OI family analyzed in this study, the
proband is designated with an arrow.
(Adapted from
9
)
he also presented hyperextensibility of the interphalan-
geal joints, mild scoliosis and mild pectus carinatum.
9
Anthropometric measurements for length were below
normal (−3.8 SD) and head circumference and weight
were within normal range for his age (−1.0 SD and
−2.0 SD, respectively). Bone densitometry performed by
dual energy X-ray absorptiometry (DEXA) revealed gen-
eralized osteoporosis (Z-score of −3.4 at the lumbar spine
and −1.9 at the femur).
Due to recurrence in a sibling and parental consan-
guinity a recessive pattern of inheritance was suggested
in this family. Microsatellite analysis in the proband, his
father and two of the unaffected siblings excluded link-
age to
COL1A1
,
COL1A2
and other recessive genes such
as
LEPRE-1
and
CRTAP
under a recessive disease model
since the patient was heterozygous for markers sur-
rounding these loci.
COL1A1
,
COL1A2
sequencing was
also negative for this patient.
To search for the causative gene we performed homo-
zygosity mapping in the proband and one of his unaf-
fected sisters using genome-wide high-density SNP
arrays (Illumina Human610-Quad BeadChip). The two
SNP genotypes generated by this process were then ana-
lyzed with Illumina software to look for blocks of homo-
zygosity. We took an arbitrary cut-off of 300 consecutive
PATIENTS REPORTED WITH
MUTATIONS IN
SP7
We reported in 2010 the case of an 8-year-old boy
with osteogenesis imperfecta (OI) born to consanguine-
ous parents related as double second cousins (
Figures
18.2 and 18.3
).
9
The family had a history of a similarly
affected sibling who in addition to OI had been diag-
nosed with a congenital heart condition and died at
the age of 4 months due to pneumonia. Fractures in
the proband started at 3 months of age and since then
occurred frequently mostly following minor trauma
with an average of 6-7 fractures per year. The child
had delayed motor milestones and he was not able to
stand unsupported. His hearing and sclerae were nor-
mal. Craniofacial features included skull with Wormian
bones, mild asymmetry of the face, high and prominent
forehead with prominent supraorbital ridges more obvi-
ous on the right side, midface hypoplasia, depressed
nasal bridge, microstomia, micrognathia and high arched
palate. Delayed teeth eruption was noted but he did not
have dentinogenesis imperfecta. X-ray examination of
the skeletal system revealed bowing of the upper and
lower limbs. His left leg was longer than his right leg and
