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FIGURE 14.2
Phenotype of the Crtap-KO mice. (A) X-ray image of adult mouse showing pronounced kyphosis and decrease bone mineral
density in Crtap-KO mice (−
/
−). (B) X-ray of hind-limb at 6 weeks of age showing profound osteopenia. (C) Section of proximal tibia stained
with H&E showing osteopenia and mild dysplasia of the growth plate (top panels). Goldner staining of trabecular bone showing decreased
presence of osteoid (in purple - middle panels). Increase diameter of collagen fibrils visualized at the TEM (lower panels).
Reproduced with copyright permission from Elsevier.
MUTATIONS IDENTIFIED IN
LEPRE1
AND
PPIB
AND PATIENT CLINICAL
DESCRIPTIONS
OI due to type I collagen mutations and that caused by
CRTAP
mutations is very difficult to make based solely
on the clinical findings and requires further biochemi-
cal or genetic investigations. Biochemically, as observed
in
Crtap−/−
mice, collagen chains secreted
in vitro
by
patients' primary skin fibroblasts showed a delayed elec-
trophoretic migration due to overmodification of pro-
line and lysine residues but also lack of 3Hyp at Proline
986 at a mass-spectrometry analysis.
11,33
Newborns with
CRTAP
mutations often develop respiratory distress
shortly after birth that can progress to respiratory insuf-
ficiency which has resulted in the majority of deaths
within the first year of life.
33,34,36
This could be due to
skeletal deformities of the thoracic cage or perhaps to a
primary defect in the lung due to abnormal type I col-
lagen in the alveoli.
16
Surviving children have intact
intellect but severe growth failure, inability to ambulate
and may develop pop-corn epiphyses in the long bones
(
Figure 14.3
) but this is not considered a specific find-
ing to these patients.
39,40
Although very few patients
with
CRTAP
mutations have been treated with bisphos-
phonates, some beneficial effects have been observed in
those individuals carrying the hypomorphic mutation
(First Nation Indians) such as increased BMD and inde-
pendent deambulation,
41
while in other instances no
significant improvement has been observed.
18
With the identification of patients with mutations in
CRTAP
and acknowledging that CRTAP forms a com-
plex with P3H1 and CYPB, many groups screened fami-
lies affected with OI of unknown etiology for mutations
in the other complex members.
The first description of patients with
LEPRE1
muta-
tions revealed a phenotype similar to OI II or OI III, with
severe osteoporosis, shortened long bones and soft skulls
with wide, open fontanelle.
42
In addition to the classic
features, these patients also presented with white sclerae,
round face and short, barrel-shaped chests (
Figure
14.3
).
42
Prenatal radiographs revealed gracile undermin-
eralized ribs and long bones. The patients that survived
after birth presented with multiple fractures, bulbous
metaphyses and matrix disorganization.
42
Complete
loss of
LEPRE1
abolished 3-hydroxylation at Proline 986
along with delayed electrophoretic mobility, indicating
collagen overmodification.42
42
The collagen produced by
patient fibroblasts had a slower secretion rate but the
total collagen secreted was higher than normal, a find-
ing previously reported with loss of
Crtap
.
11,42
Findings
from other patients include white sclerae, severe growth
