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the complex are able to initiate de-capping of the mRNA
and susceptibility to exonucleases which leads to loss
of stable mRNA from that allele. This occurs regardless
of the mechanism by which a premature termination
codon is introduced.
generally do not result in a phenotype that brings people
to medical attention. The frequency of
COL1A1
muta-
tions in the general population is probably on the order of
1
/
20,000-25,000 individuals based on a prevalence of OI
of about 1
/
10,000-12,000 individuals and the assumption
that they account for about half of affected individuals.
There are no
COL1A2
haploinsufficiency mutations noted
in the exome variant server (
http:
//
evs.gs.washington.
viduals (13,000 alleles). This database contains a wide
variety of individuals with recognizable high-frequency
disorders in the general population but would not be
expected to exclude this class of mutations if they result
in phenotypes only in the homozygote or compound het-
erozygote. Thus it probably establishes a minimal esti-
mate of allele frequency. A more assertive examination of
an extended phenotype may be necessary to identify the
clinical effects of heterozygosity for
COL1A2
mutations.
FREQUENCY OF HAPLOINSUFFICIENCY
MUTATIONS IN THE TYPE I COLLAGEN
GENES
The frequency of haploinsufficiency mutations iden-
tiied in
COL1A1
and
COL1A2
is markedly different.
While they constitute the major class of mutations in
COL1A1
they are rarely seen in
COL1A2
. The first muta-
tion identified in OI was homozygosity for a mutation
in
COL1A2
that led to a frameshift near the 3′ end of the
coding region that abolished the ability of the pro-α2(I)
chains to assemble into the trimer.
4
Cultured cells from
this child made type I procollagen that contained only
pro-α1(I) chains with the consequence that he had an OI
type III-IV clinical picture. The mRNA in this instance
was stable but the encoded protein chains were very
unstable. The only mutations in
COL1A2
that lead to
mRNA instability result in a rare clinical picture of a form
of Ehlers-Danlos syndrome associated with polyvalvular
insufficiency.5
5
Heterozygosity for those mutations may be
associated with joint hypermobility but this class of muta-
tion is not present among individuals with isolated joint
hypermobility who have been tested. Heterozygosity for
COL1A1
haploinsufficiency mutations results in OI type I.
Homozygosity results in an embryonic lethal phenotype
in mice and so is not expected and has not been seen in
humans.
The reason that heterozygosity for
COL1A2
haploin-
sufficiency mutations is very rarely encountered is not
entirely clear. The opportunity to create them is similar to
that in
COL1A1
. The most likely explanation is that they
References
