Biomedical Engineering Reference
In-Depth Information
13.5
Defective rRNA Modi fi cations in Human Diseases
The development of a faithful mouse model of X-DC has provided significant
insights into the role of rRNA pseudouridylation in the control of gene expression
at the translational level (Ruggero et al.
2003
). More importantly, human genetic
studies also highlight an important role for the Y synthase dyskerin in translation
control. Specifically, the inherited disease X-linked Dyskeratosis Congenita (X-DC)
is caused by mutations in the gene encoding the Y synthase dyskerin (Heiss et al.
1998
) and cells derived from X-DC patients exhibit specific translation defects that
explain, in part, some of the severe pathological features of the disease (Bellodi
et al.
2010a
; Yoon et al.
2006
). In addition to X-DC, the contribution of “aberrant”
protein synthesis toward the pathogenesis of human diseases has recently under-
gone a paradigm shift with the identification of an entire class of inherited human
syndromes termed “ribosomopathies” (Narla and Ebert
2010
) . Patients suffering
from these diseases, which are associated with mutations in distinct components of
the translational apparatus including rRNA synthesis and processing factors, ribo-
some assembly factors, and ribosomal proteins, share several common clinical fea-
tures such as bone marrow failure (BMF), skeletal defects, and increased susceptibility
to cancer. It remains to be determined if common translational impairments may be
responsible for some of the recurrent pathological features present in ribosomopa-
thies (Ganapathi and Shimamura
2008
). Research focused on identifying the
downstream targets affected by aberrant translational control of gene expression
will undoubtedly provide the rationale for new therapies and treatment options for
patients suffering from these diseases. In this section, we will highlight some
important findings on how reductions in rRNA modifications may contribute to
human diseases.
13.5.1
X-Linked Dyskeratosis Congenita
X-DC is a rare inherited human syndrome invariably associated with point muta-
tions in the DKC1 gene locus on chromosome Xq28 (Heiss et al.
1998
) . From a
clinical standpoint, X-DC is characterized by a wide spectrum of pathological fea-
tures including a triad of cutaneous defects: abnormal skin pigmentation, nail dys-
trophy, and oral leukoplakia; a variety of non-cutaneous dental, gastrointestinal,
genitourinary, neurological, ophthalmic, pulmonary, and skeletal defects; and severe
hematological dysfunctions (Dokal
2000
; Kirwan and Dokal
2008
) . BMF associ-
ated with peripheral cytopenia, in one or more hematopoietic cell lineages, repre-
sents the primary cause of early mortality in X-DC patients along with high
susceptibility to solid and hematological malignancies (Alter et al.
2009
; Marsh
et al.
1992
; Montanaro
2010
). The clinical features of the disease normally appear
in childhood with up to 90 % of patients showing signs of BMF by the age of 30
years. Notably, X-DC is the most severe form of Dyskeratosis Congenita, although
Search WWH ::
Custom Search