Biology Reference
In-Depth Information
Adar1
/
phenotype could be rescued
by the expression of ADAR1 and rescue was largely dependent on RNA-editing
activity (XuFeng
development (Hartner
et al.
, 2009). The
, 2009). Recent work (Vitali and Scadden, 2010) has
shown that I-U-containing dsRNA inhibits the induction of an interferon
response by binding to the cytosolic dsRNA receptors RIG1 and MDA5, suggest-
ing that ADAR1 may act to restrain or to terminate interferon responses.
et al.
2. Human mutations in the
gene
Several human mutations distributed across the entire ADAR1 gene cause the
relatively benign dyschromatosis symmetrica hereditaria (DSH) (Liu
ADAR1
et al.
, 2006;
Miyamura
, 2004, 2008) which is an autosomal dominant
skin pigmentation disorder that predominantly affects the hands and feet. The
discovery of 30 different point mutations in the ADAR1 gene associated with
this disorder indicates that ADAR1 has an as yet undefined role in melanocyte
development or pigmentation. The disease arises from haploinsuffiency of the
remaining
et al.
, 2003; Zhang
et al.
gene copy. Some mutations are truncations within the N-
terminal region unique to ADAR1 p150, suggesting that loss of this isoform
alone is sufficient to cause disease. One individual with the disorder had a
mutation, G1007R, which is in a highly conserved region that lies within the
deaminase domain (Tojo
ADAR1
, 2006). This individual also presented with
chronic dystonic posture and calcification in the brain. Functional assays demon-
strated that the G1007R mutant protein is not capable of RNA editing although
it retains RNA-binding activity, indicating it may behave as a dominant nega-
tive mutant with the strongest
et al.
ADAR1
loss of function phenotype yet seen in
humans (Heale
, 2009a,b). This mutation has subsequently been found in
another individual with DSH, dystonia, and calcinosis of the brain; however, the
mother who carried the mutation did not have neurological symptoms which
suggests that this mutation may have reduced penetrance (Kondo
et al.
et al.
, 2008).
B. ADAR2
ADAR2 has a very similar domain structure to ADAR1 with two dsRBDs at the
amino terminus and the catalytic deaminase domain at the C-terminus
(Fig. 3.2). This protein is more conserved than ADAR1 and its ortholog is
found in
, 2000). It is a nuclear protein, and like
ADAR1 p110, it has been shown to localize to the nucleolus in a dynamic
manner (Dawson
Drosophila
(Palladino
et al.
, 2003). Further investigation
revealed that a region encompassing the first dsRBD is required for nucleolar
localization, and the ADAR2 protein relocalizes to the nucleoplasm upon
expression of a substrate. However, it is unclear whether the region harbors a
et al.
, 2004; Desterro
et al.
