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TABLE 17.1
Identified
SERPINF1
Mutations in Patients with
Osteogenesis Imperfecta
The standard treatment of OI is bisphosphonate
therapy. Bisphosphonates are synthetic pyrophosphate
analogs known to bind to the mineralized surface and
inhibit osteoclasts. This leads to decreased bone resorp-
tion and hence decreased bone turnover markers that are
used to follow response to therapy in patients. Patients
with OI type VI did not respond as well to bisphospho-
nate therapy when compared to controls with other
types of OI. There were improvements in bone mineral
mass, gross motor functions and fracture incidence in
children and adolescents treated with cyclical IV pami-
dronate for 3 years, but the improvements were less than
in controls with other types of OI. The limitations of this
study include a small cohort of only ten children and
adolescents and a short duration of the study.
12
Recently, denosumab (a RANKL antibody) was
approved for treatment for postmenopausal osteoporo-
sis.
13
Since there is suboptimal response to bisphospho-
nate therapy in OI VI patients, denosumab was recently
used in four children with OI type VI at a dose of 1 mg/kg
s.c. every 3 months.
14
Markers of bone resorption
decreased to the normal range after each injection but
reached pretreatment levels 6-8 weeks after the injec-
tion. The drug was well tolerated, but a small cohort and
a short duration of therapy limited the study. Although
there is a need for a direct comparison between these two
drugs in OI type VI, it suggests that denosumab may be
used as a therapeutic option for OI type VI patients who
do not respond well to standard bisphosphonate therapy.
Reference
DNA Change
Mutation Type
Protein Change
Shaheen et al.
8
c.-9+2dup
Splice site
Tucker et al.
9
and Rauch
et al.
10
c.271_279dup
In-frame
insertion
p.Ala91_
Ser93dup
Homan et al.
7
and Rauch
et al.
10
Nonsense
p.Arg99*
c.295C>T
Becker et al.
6
c.324_325dup
Frameshift
p.Tyr109Serfs*5
Venturi et al.
11
c.423delG
Frameshift
p.Ile142Serfs*9
Rauch et al.
10
c.439+127_643
+545del
In-frame
deletion/
insertion
p.Lys147_
Gly215delinsArg
Shaheen et al.
8
c.653del
Frameshift
p.Val218Glufs*22
Becker et al.
6
c.696C>G
Nonsense
p.Tyr232*
Rauch et al.
10
c.829_831del
In-frame
deletion
p.Phe277del
Shaheen et al.
8
c.1118_1119del
Frameshift
p.Pro373Glnfs*18
Becker et al.
6
c.1132C>T
Nonsense
p.Gln378*
Homan et al.
7
c.1163_1166dup
Frameshift
p.His389Glnfs*4
(PEDF). Serum PEDF levels were undetectable in patients
with OI type VI as compared to other OI patients with
type I collagen mutations. More recently, additional
mutations in
SERPINF1
were identified in patients with
OI type VI (
Table 17.1
).
8-11
Since the only feature distinguishing OI type VI from
other types of OI is from bone biopsy results, there is
a need for non-invasive diagnostic testing, especially in
children. It is important to identify the type of OI since
it has implications on the prognosis and the manage-
ment of the patients. Homan et al. showed that patients
with OI type VI mutations had no detectable PEDF in
their sera, which indicated that screening for serum
levels of PEDF could be a possible diagnostic tool.
7
In
2012, Rauch et al. suggested measurement of serum
PEDF (by ELISA) as a screening tool for diagnosis of
OI type VI, since it was specific to this type of OI.
10
In
that study, serum PEDF concentration did not corre-
late with bone turnover or the mineralization process.
Bisphosphonate therapy also did not influence the
serum levels of PEDF. This indicated that PEDF is not
a good marker for follow-up, but it could be potentially
used for diagnosis of OI type VI even if patients have
been previously treated or are currently being treated
with bisphosphonates. Serum concentration of PEDF
was positively associated with serum creatinine and
BMI z-score and negatively associated with OI severity.
This phenomenon is incompletely understood.
PEDF: IDENTIFICATION, STRUCTURE
AND FUNCTION
PEDF is expressed in various tissues in humans
and mice such as eye, liver, heart, adipose tissue and
bone.
15-17
PEDF was first discovered by Tombran-Tink
and Johnson in the conditional medium from the cul-
ture of fetal human retinal pigment epithelium.
18
Their
study showed that PEDF could induce neuronal differen-
tiation of human Y79 retinoblastoma cells. For example,
treatment of PEDF induced neurite outgrowth and the
expression of neuron-specific enolase as well as neuro-
filament proteins. This discovery indicated that PEDF
functions as a strong neurotrophic factor. Further analy-
sis of amino acid and DNA sequence revealed that PEDF
is a member of the serine protease inhibitor (serpin)
superfamily; however, PEDF lacks the serine protease
inhibitory activity.
19,20
In addition to its function as a neu-
rotrophic factor, further studies have shown that it also
functions as a neuroprotective factor. For example, PEDF
inhibited the apoptosis induced by hydrogen peroxide in
retinal neurons, and intravitreal injection of PEDF pro-
tected rat photoreceptors from light damage.
21,22
Besides
the eye, PEDF prevented glutamate-induced damage in
