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In Depth Tutorials and Information
CHAPTER
58
New Discoveries in Osteogenesis
Imperfecta
Jay R. Shapiro
Johns Hopkins School of Medicine, Kennedy Krieger Institute, Baltimore, MD, USA
INTRODUCTION
other new OI-related genes is yet to be realized. The lim-
ited phenotypic expression of the multiplicity of mutated
genes illustrates the complexity of a process of gene
expression we have yet to fully understand.
The virtual explosion of next-generation sequencing
technologies has led to a sea change in the approach to
the sequencing of human genomes and exomes.
1
Large-
scale automated DNA sequencing can now be accom-
plished relatively rapidly and at comparatively low cost
compared to the Sanger sequencing method which was
the standard for several years. As an example, Sule et al.
have recently reported on the design and application of a
next generation sequencing (NSG) platform that permits
simultaneous sequencing on a single platform of multiple
different genes associated with OI, and other inherited
connective tissue genes associated with either low or high
bone mineral density.
2
Since the initial definition of four OI types by Sillence
et al., research has focused on the role of mutant proteins
associated with type I collagen synthesis.
3
Advances in
gene discovery, particularly with the advent of whole
exome sequencing, have led to the identification of
several genes not primarily associated with type I col-
lagen synthesis. These present a phenotype that is con-
sistent with moderately severe osteogenesis imperfecta
(OI). Chapter 20 reviews mutations in the gene IFITM5
(OMIM #614757) in type V OI and the variable expres-
sion of the phenotype associated with these mutations.
IFITM5 (interferon-induced transmembrane protein) is
another example of a protein related to osteoblast devel-
opment but outside the traditional collagen synthetic
pathway. In this discussion we will describe two recently
defined gene products and their associated phenotypes
which are not discussed in depth elsewhere in this topic.
Including the involvement of these genes with the OI
phenotype illustrates the point that the discovery of
TMEM38B AND OI
This gene encodes the trimeric intracellular cation
channel type B (TRIC-B). TRIC-B is present at relatively
low levels throughout the sarco-/endoplasmic reticu-
lum and nuclear membranes. The electrophysiological
data indicate that TRIC channels behave as K(+) channels
under intracellular conditions, although the detailed chan-
nel characteristics remain to be investigated. The patho-
physiological defects detected in knockout mice suggest
that TRIC-B channels support sarco-/endoplasmic reticu-
lum Ca(2+) release mediated by ryanodine (RyR) and
inositol trisphosphate receptor (IP(3)R) channels. Current
evidence strongly suggests that TRIC channels mediate
counter-K(+) movements, in part, to facilitate physiologi-
cal Ca(2+) release from intracellular stores.
4
Yazawa et al.
have reported that TRIC-B-null mice showed neonatal
lethality but the bone phenotype has not been described.
5
This gene was mapped to chromosome 9q31.2.
6
The
phenotype is listed as OI type XIV in OMIM (#615066);
however, this designation is open to question as dis-
cussed in Chapter 2 where the issue of assigning another
OI “number” as each new mutation is defined is pre-
sented. The phenotype in cases reported to date is con-
sistent with moderately severe OI and may have been
considered as Sillence type IV prior to gene definition.
It is notable that the initial two reports of TMEM38B
mutations involved consanguineous kindreds from
