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Blood, 1 March 2002, Vol. 99, No. 5, pp. 1811-1816
RED CELLS
Abnormally spliced  -globin mRNAs: a single point mutation
generates transcripts sensitive and insensitive to nonsense-mediated
mRNA decay
Sven Danckwardt,
Gabriele Neu-Yilik,
Rolf Thermann,
Ute Frede,
Matthias W. Hentze, and
Andreas E. Kulozik
From the Department of General Pediatrics,
Charité, Humboldt-University, Berlin; and the Gene Expression
Program, EMBL, Heidelberg, Germany.
Nonsense-mediated mRNA decay (NMD) represents a phylogenetically
widely conserved splicing- and translation-dependent mechanism that
eliminates transcripts with premature translation stop codons and
suppresses the accumulation of C-terminally truncated peptides. Elimination of frameshifted transcripts that result from faulty splicing may be an important function of NMD. To test this hypothesis directly, this study used the IVS1 + 5 G>A thalassemia
mutation of the human  -globin gene as a model system. We generated
-globin gene constructs with this mutation and an iron-responsive
element in the 5' untranslated region, which allowed specific
experimental activation and inactivation of translation and, hence, NMD
of this transcript. Premessenger RNAs with IVS1 + 5 G>A were spliced at normal sites and cryptic sites, enabling a direct comparison of the
effect of NMD on the accumulation of normal and frameshifted messenger
RNAs. In transfected HeLa cells, the predominant frameshifted transcript was degraded under conditions of active NMD, whereas accumulation to high levels occurred under conditions of specifically disabled NMD, thereby indicating an important physiologic function of
NMD in the control of the splicing process. An unexpected finding was
that accumulation of a second aberrant transcript remained unaffected
by NMD. The IVS1 + 5 G>A mutation thus revealed the presence of an
unknown cis-acting determinant that influences the NMD
sensitivity of a putative NMD substrate. It can therefore serve as a
useful tool for defining the mechanisms that permit specific
transcripts to circumvent the NMD pathway.
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