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CHAPTER
17
SERPINF1 as a Cause of Osteogenesis
I mperfecta Type V I
Kyu Sang Joeng, Monica Grover, Abbhirami Rajagopal and
Brendan H. Lee
Baylor College of Medicine, Houston, TX, USA
OSTEOGENESIS IMPERFECTA TYPE VI
AND SERPINF1
The histological characteristics of OI type VI are some-
what similar to osteomalacia, which is best known to be
caused by calcium or vitamin D deficiency. The defective
mineralization is apparent in growth plates of patients
with osteomalacia, clinically presenting as rickets, but it
is absent in patients with OI type VI. The abnormality in
mineralization in OI type VI is restricted to bone matrix
and does not appear to affect the cartilage.
For almost a decade after the clinical description of
OI type VI, there was still no identified genetic cause.
In 2011, Becker et  al. identified mutations in the gene
SERPINF1 in four patients with autosomal recessive OI
type III using whole exome sequencing. 6 The mutations
included nonsense and frameshift mutations leading to
premature stop codons, and both mutation types were
predicted to lead to nonsense-mediated decay of mRNA.
There was also a nonsense mutation in the last coding
exon of this gene in one patient, which was not predicted
to undergo nonsense-mediated decay. These patients pre-
sented with their first fractures at 4-6 months of age and
had grayish sclera, short stature and long bone deformi-
ties due to multiple fractures. However, they did not have
dentinogenesis imperfecta. The diagnosis of OI type VI
was not considered in these patients as bone pathology
was not reported. Concurrently, Homan et  al. identified
mutations in the same gene by homozygosity mapping
and next-generation sequencing in three patients with OI
type VI from a French Canadian consanguineous family.
These patients were diagnosed by the presence of charac-
teristic features on bone histomorphometry underscoring
the requirement for bone pathology to make this clini-
cal diagnosis. 7 SERPINF1 encodes for a 50 kDa secreted
glycoprotein termed pigment epithelium-derived factor
Osteogenesis imperfecta (OI) is a heritable disease
characterized by bone fragility and low bone mass.
Ninety to 95% of the cases are caused by mutations in
genes coding for type I collagen ( COL1A1 and COL1A2 ).
The other 5-10% are a heterogeneous group caused by
mutations in genes involved in collagen processing, post-
translational modification and transport such as CRTAP ,
LEPRE1 , FKBP10 , PLOD2 , SERPINH1 , PPIB and SP7 .
There are potentially other unknown OI genes remaining
to be identified. OI was originally classified by Sillence
into four types but was later expanded to seven types
based on inheritance and clinical features. 1-4 There is still
no consensus on classification based on genetic etiology. 5
In 2002, Francis Glorieux first described the OI type VI
form in a group of patients initially classified as OI type
I V. 2 Overall, these patients sustained more fractures than
OI type IV patients but were normal at birth, experienc-
ing their first fracture between 4 and 18 months of age.
These patients did not show dentinogenesis imperfecta,
had white or faintly blue sclerae and half of the patients
presented with ligamentous laxity.
The diagnosis was made on the basis of bone biopsy
results that showed loss of the normal lamellation pat-
tern of the bone with a fish scale appearance under polar-
ized light. The characteristic histomorphometric feature
was an abundance of unmineralized bone or osteoid in
OI type VI as compared to other types of OI. This was
suggestive of defective mineralization. Other types of
OI can also show increased osteoid surface but they dis-
play normal osteoid thickness due to a high turnover.
 
 
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