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CHAPTER
12
Haploinsufficiency for Mutations in
Type I Collagen Genes: Mechanisms and
Clinical Effects
Peter H. Byers
University of Washington, Seattle, WA, USA
INTRODUCTION
COLLAGEN PROTEIN STRUCTURE,
GEN
ES AND TYPE OF MUTATI
ONS
In general for dominantly inherited disorders, the
prevalence is related to longevity and fertility. As a
corollary, the frequency of new dominant mutations is
inversely proportional to lifespan. Osteogenesis imper-
fect (OI) represents no exception in this regard. For the
perinatal lethal dominant form (OI type II) that results
from type I collagen mutations, the most affected indi-
viduals are those who have new mutations (the excep-
tions being the proportion that result from parental
mosaicism),
1
a small group who have biallelic muta-
tions that result in recessive OI,
2
and the incidence
of new mutations among people with other forms of
OI which is inversely proportional to lifespan and the
chance to reproduce.
About 95% of individuals with OI have the condi-
tion as a result of dominant mutations in the two type I
collagen genes,
COL1A1
and
COL1A2
(OI and Ehlers-
Danlos syndrome variant databases:
http:
//
www.le.ac.
the nature of the mutation, the region of the gene or
the encoded protein affected, and the gene or protein
affected, all influence the phenotypic expression and
the type of OI that results. The rules that determine
phenotypic outcomes have not been worked out com-
pletely so that, if a mutation has not been seen previ-
ously, it both adds to the database on which to provide
predictive data and provides additional data on which
to determine how the effects can be inferred from muta-
tions in the surrounding region of the same gene or in
the general domain encoded by each of the genes.
Type I collagen is a heterotrimer that consists of two
α1(I) chains and a single α2(I) chain, encoded by the
COL1A1
and
COL1A2
genes, respectively. Each of the
precursor proα chains contains an initiator methionine,
a signal sequence that is cleaved during processing, a
propeptide that contains a short triple helical domain
(45 amino acids with a Gly-Xaa-Yaa repeating sequence
motif), a transition sequence that contains the propep-
tide cleavage sequence, the major triple helix of 1014
residues, a short telopeptide, and the propeptide that
is essential for chain-chain recognition and assembly
of the trimer that then is assembled to form the charac-
teristic triple-helical domain of the protein. The glycine
residues in the major triple-helical domain are essential
to correct folding of the domain and any substitution
will result in an OI phenotype. Of the 338 glycines in the
major domain, substitutions have been identified in the
majority, but less than half of the calculated 2200 or so
possible substitutions in each gene that result from sin-
gle nucleotide alteration in glycine codons (GGN) have
been identified. In this region of coding sequence two
of every nine nucleotides, when substituted, will result
in a clinically recognizable OI phenotype - a total of 776
nucleotides in each gene. Mutations in the two canoni-
cal residues of both the acceptor and donor splice sites
of each intron provide another source of mutations that
can have a number of different types of outcome, each of
which will usually result in an OI phenotype. The excep-
tion known to this rule are the mutations that result in
