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VOL. 72 (4), 563-581, 2006 ABERRANT MRNA STABILITY REGULATION IN HUMAN...

Thalassemia

Thalassemia is a hereditary anemia resulting from defects in

hemoglobin production. It is considered the most common genetic

disorder worldwide. Thalassemia is clinically heterogeneous because

multiple genetic lesions have been described to variably impair

globin-chain synthesis. In the normal adult, hemoglobin A, which is

composed of two alpha and two beta globins (a2ß2), is the most
prevalent, comprising about 95% of all hemoglobin. The thalassemias

are classified according to which chain of the globin molecule is
affected. An a-globin gene variant, a constant spring (a cs), is the
most common cause of nondeletional a-thalassemia worldwide. The
a cs mutations harbors a single nucleotide substitution at the wild-
type a-globin mRNA (a WT) translational stop codon (UAA to CAA).
This mutation allows the ribosomes to translate into the normally

ribosome-free 3’UTR, causing a major decrease in a-globin mRNA
half-life. Searching for the mechanisms responsible for the
accelerated decay of the a cs mRNA, Morales and colleagues found
that the a cs mRNA poly(A) tail was significantly shorter that the a WT
mRNA poly(A) tail. Therefore, reduced a cs mRNA half-life appeared
to be linked to accelerated 3’ terminal deadenylation (24). Moreover,
insertion of a stop codon into the a cs immediately upstream of the
a cs mutation prevented ribosome entry into the 3’UTR and stabilized
the a cs mRNA. This data supported a model in which a stability
determinant was present in the 3’UTR and could be affected by the

elongating ribosome (25). In fact, analysis of this region identified

three cytosine-rich (C-rich) segments [also known as pyrimidin-rich

element (PRE)] that contributed to a-globin mRNA stability when
studied in transfected erythroid cells. Subsequently in vitro studies

demonstrated assembly of a sequence-specific ribonucleic-protein

(RNP) complex at this site. Members of the a-globin poly(C)-binding
protein (aCP) were identified as essential protein components of
the a-complex. In patients who have the a cs mutant, read through
translation of the 3’UTR prevents the PCBPs from binding to the

C-rich elements. In vitro studies suggested that additional proteins

may also contribute to a-complex structure and/or function. Of
particular interest was the identification of the ARE binding/

degradation factor AUF1 and poly(A)-binding protein (PABP) as an

interacting partners of aCPs (25).

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