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sequenced three clones. One clone contained a single
base substitution that changed the codon for glycine
988 to a cysteine.
42
This seems a remarkable effort
when compared to automated RT-PCR and sequenc-
ing approaches available today that can screen the
entire collagen genes for mutations in a day or two. A
different but equally complex approach was used to
identify the second glycine mutation, a glycine 391 to
arginine substitution. The patient had a charge change
in the CB8 peptide
38,39
and so the peptide was purified
from patient bone in multiple chromatography steps,
digested with trypsin, further purified and sequenced.
44
Mutation detection remained laborious, relying on pro-
tein changes to narrow the search and requiring prepa-
ration and screening of cDNA libraries,
45,46
until the
introduction of PCR and commercially available Taq
polymerase in the early 1990s revolutionized mutation
detection.
Both amino acid sequencing of peptide fragments
and then positional cloning and sequencing of cDNA
and genomic DNA had by the early 1990s completely
transformed our understanding of the pathogenesis
in some 85% of patients with OI. One could general-
ize that OI type I resulted from mutations which were
either nonsense mutations, indels resulting in frame-
shifts which ultimately result in generation of a novel
stop codon, or splicing mutations. Splicing mutations
account for approximately one-third of mutations
in patients with OI type I and nonsense and frame-
shift mutations together account for the remaining
two-thirds.
47
On the other hand, a continuum of phe-
notypes resulting in mild to moderately severe OI,
through progressively deforming and encompassing
extremely severe perinatally lethal OI, resulted pre-
dominantly from missense mutations in type I collagen
genes.
47
However, in some 15% of cases no abnormal-
ity was found in the helical coding regions of COLIA1
or COLIA2. Virtually no type I collagen gene mutations
had been described in cases where classic genetic analy-
sis predicted that the disorder was inherited as an auto-
somal recessive trait.
Simultaneously with the major advances in collagen
protein investigative technologies and insights into the
DNA molecular mechanisms which might explain the
abnormalities in collagen protein structure and func-
tion, progress had been made with describing the clini-
cal and genetic heterogeneity in OI. This culminated in
the population genetic studies and the nosology and
classification published in 1979 by Sillence and col-
leagues which grouped OI syndromes by primary clini-
cal characteristics and pattern of inheritance into four
groups, OI types I-IV.
48
The most important feature
of this nosology is that it identified specific syndrome
groups within the broad spectrum of presentations of
OI which in the majority of instances were reproduced
regularly within families and rarely showed over-
lap between families, thus providing a grouping
which facilitated basic research into mechanisms of
pathogenesis.
Although nomenclature revisions in the past 30
years have seen the proposed numbers of OI syn-
dromes being increased up to OI type XII, at the 2009
meeting of the International Nomenclature group for
Constitutional Disorders of the Skeleton, a decision
was made to group the known OI syndromes into five
groups, i.e., preserving the primary four groups and
adding a fifth type of OI, OI with calcification of inter-
osseous membranes first described by Battle and col-
leagues in 1908.
49
The newer disorders and all the
known molecular defects which further extend the
genetic heterogeneity are encapsulated as subtypes of
one of these phenotypic groupings (
Tables 1.1-1.2
).
50
In the words of the Nomenclature Committee which
is a standing committee of the International Congresses
of Human Genetics:
Group 25 (Osteogenesis Imperfecta and decreased bone
density group) has had special attention. The Sillence clas-
sification, published 30 years ago, provided a first systematic
clinical classification and made correlations to the inheritance
pattern of individual clinical types [Sillence et al.,
48
]. Today, a
surprising genetic complexity of the molecular bases of OI has
been revealed, and at the same time the extensive phenotypic
variation arising from single loci has been documented clearly.
It seemed therefore untenable to try and maintain tight correla-
tions between “Sillence types” and their molecular basis. It was
agreed upon to retain the Sillence classification as the proto-
typic and universally accepted way to classify…OI; and to free
the Sillence classification from any direct molecular reference.
Thus, the many genes that may cause osteogenesis imperfecta
have been listed separately. The proliferation of “OI types” to
reflect each gene separately, advocated by some scholars, is
more confusing than helpful in clinical practice.
TABLE 1.1
The Recommended Nomenclature of OI Syndromes
INCCDS 2010
Equivalent
Numerical Type
Syndrome Names
a
Subtypes
Classic non-deforming OI with blue
sclerae
I
2
Common variable OI with normal
sclerae
IV
2
OI with calcification in interosseous
membranes
V
1
Progressively deforming OI with
normal sclera
III
12
Perinatally lethal OI
II
6
a
In this table the syndromes are listed roughly in order of increasing severity of fracture
tendency and skeletal deformity.
