Osteogenesis imperfecta (OI) (“brittle bone disease”)
is a heterogeneous group of clinically and
genetically different types of diseases with a
total frequency of at least 1 in 10 000 individuals.
Spontaneously occurring bone fractures,
bone deformity, small stature, defective dentition
(dentinogenesis imperfecta), hearing impairment
due to faulty formation of the auditory
ossicles, and blue sclerae (the fully
developed conjunctiva of the eye is thinner than
normal, so that refracted light is shifted toward
blue) occur in the various forms to different extents
and with different grades of severity, depending
on the type of mutation.
Sunday, April 12, 2009
Molecular mechanisms in osteogenesis imperfecta
Some types of mutation may lead to reduced
production of pro!1(I) (1 and 2), e.g., deletion of
a COL1A1 allele, a transcription or splicing defect,
or faulty formation of collagen fibrils. The
relative excess of pro!2(I) molecules becomes
degraded. Thus, less procollagen than normal is
formed, but it is not defective. Numerous other
types of mutations can lead to defective procollagen
(3). Mutations in the pro!1(I) gene are
more severe than mutations in the pro!2(I)
gene because a greater amount of defective collagen
is formed.
production of pro!1(I) (1 and 2), e.g., deletion of
a COL1A1 allele, a transcription or splicing defect,
or faulty formation of collagen fibrils. The
relative excess of pro!2(I) molecules becomes
degraded. Thus, less procollagen than normal is
formed, but it is not defective. Numerous other
types of mutations can lead to defective procollagen
(3). Mutations in the pro!1(I) gene are
more severe than mutations in the pro!2(I)
gene because a greater amount of defective collagen
is formed.
Mutations and phenotype
The location of a mutation in the gene influences
the phenotype. Generally, mutations
in the 3! region aremore serious than mutations
in the 5! region (position effect). Mutations of
the pro!1(I) chain are more severe than those
in the pro!2(I) chain (chain effect). The substitution
of a larger amino acid for glycine, which
is indispensable for the formation of the triple
helix, leads to severe disorders (size effect).
Different types of mutations may occur, such as
deletions, mutations in the promoter or enhancer,
and splicing mutations. The codons
(AAG, AAA) for the amino acid lysine, which occurs
frequently in collagen, are readily transformed
into a stop codon by substitution of the
first adenine by a thymine (TAG or TAA), so that
a short, unstable procollagen is formed.
the phenotype. Generally, mutations
in the 3! region aremore serious than mutations
in the 5! region (position effect). Mutations of
the pro!1(I) chain are more severe than those
in the pro!2(I) chain (chain effect). The substitution
of a larger amino acid for glycine, which
is indispensable for the formation of the triple
helix, leads to severe disorders (size effect).
Different types of mutations may occur, such as
deletions, mutations in the promoter or enhancer,
and splicing mutations. The codons
(AAG, AAA) for the amino acid lysine, which occurs
frequently in collagen, are readily transformed
into a stop codon by substitution of the
first adenine by a thymine (TAG or TAA), so that
a short, unstable procollagen is formed.
Different forms of osteogenesis imperfecta
Osteogenesis imperfecta may be classified according
to severity into four basic phenotypes
(Sillence classification). Although the classification
does not correspond to the types of mutation,
it has in general proved clinically useful. Ol
types I and IV are less severe than type II (lethal
in infancy) and type III. Three radiographs show
a relatively mild (but for the patient nevertheless
very disabling) deformity of the tibia and
fibula in Ol type IV (1); severe deformities in the
tibia and fibula in Ol type III (2); and the distinctly
thickened and shortened long bones in
the lethal Ol type II (3). Mutations in Ol are
autosomal dominant, the severe forms being
due to de novo mutations. Germline mosaicism
has been shown to account for rare instances of
affected siblings being born to unaffected
parents.
to severity into four basic phenotypes
(Sillence classification). Although the classification
does not correspond to the types of mutation,
it has in general proved clinically useful. Ol
types I and IV are less severe than type II (lethal
in infancy) and type III. Three radiographs show
a relatively mild (but for the patient nevertheless
very disabling) deformity of the tibia and
fibula in Ol type IV (1); severe deformities in the
tibia and fibula in Ol type III (2); and the distinctly
thickened and shortened long bones in
the lethal Ol type II (3). Mutations in Ol are
autosomal dominant, the severe forms being
due to de novo mutations. Germline mosaicism
has been shown to account for rare instances of
affected siblings being born to unaffected
parents.
Molecular Basis of Bone Development
The skeleton develops from mesodermal cells
committed to differentiate into three specialized
cell types: chondrocytes (cartilage-forming
cells), obsteoblasts (bone-forming cells),
osteoclasts (bone-degrading cells), and their
precursor cells. Osteoblasts produce most of the
proteins for the extracellular bone matrix and
control its mineralization. The osteoblast cell
lineage involves osteoblast-specific transcription
factors (OSFs). One such transcription factor
was identified in 1997 as a major regulator
of osteoblast differentiation, the core-binding
factor Cbfal.
committed to differentiate into three specialized
cell types: chondrocytes (cartilage-forming
cells), obsteoblasts (bone-forming cells),
osteoclasts (bone-degrading cells), and their
precursor cells. Osteoblasts produce most of the
proteins for the extracellular bone matrix and
control its mineralization. The osteoblast cell
lineage involves osteoblast-specific transcription
factors (OSFs). One such transcription factor
was identified in 1997 as a major regulator
of osteoblast differentiation, the core-binding
factor Cbfal.
The mouse Cbfal transcription
The mouse Cbfal transcription factor (the
human counterpart is referred to as CBFA1) is a
member of the runt-domain family. The runtdomain
is a DNA-binding domain homologous
to that produced by the Drosophila pair-rule
gene runt.
human counterpart is referred to as CBFA1) is a
member of the runt-domain family. The runtdomain
is a DNA-binding domain homologous
to that produced by the Drosophila pair-rule
gene runt.
Effects of homozygous Cbfa1 mutations on the mouse skeleton
Targeted disruption of the Cbfa1 gene in the homozygous
state (!/!) results in a severe phenotype.
Homozygous mutant mice are small and
die from respiratory failure at birth. In contrast
to normal mice (+/+, 1), the mutant mice (!/!, 2)
completely lack bone development, as shown
by lack of alizarin red staining. Just before birth,
normal +/+ mouse embryos (3) show welldeveloped
bones (stained red) in the upper extremities,
including the clavicles (arrow) and
the tuberositas humeri (circle). Heterozygous
mice (+/!, 4) show severe hypoplasia and reduced
ossification of the long bones. Homozygous
mutant mice (!/!, 5) totally lack any bone
formation, as shown by lack of red staining.
state (!/!) results in a severe phenotype.
Homozygous mutant mice are small and
die from respiratory failure at birth. In contrast
to normal mice (+/+, 1), the mutant mice (!/!, 2)
completely lack bone development, as shown
by lack of alizarin red staining. Just before birth,
normal +/+ mouse embryos (3) show welldeveloped
bones (stained red) in the upper extremities,
including the clavicles (arrow) and
the tuberositas humeri (circle). Heterozygous
mice (+/!, 4) show severe hypoplasia and reduced
ossification of the long bones. Homozygous
mutant mice (!/!, 5) totally lack any bone
formation, as shown by lack of red staining.
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