Nonsense mutations in the human beta-globin gene affect mRNA metabolism.

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Abstract
A number of premature translation termination mutations (nonsense mutations) have been described in the human .alpha.- and .beta.-globin genes. Studies on mRNA isolated from patients with .beta.o-thalassemia have shown that for both the .beta.-17 and the .beta.-39 mutations less than normal levels of .beta.-globin mRNA accumulate in peripheral blood cells. (The codon at which the mutation occurs designates the name of the mutation; there are 146 codons in human .beta.-globin mRNA.) In vitro studies using the cloned .beta.-39 gene have reproduced this effect in a heterologous transfection system and have suggested that the defect resides in intranuclear metabolism. We have asked if this phenomenon of decreased mRNA accumulation is a general property of nonsense mutations and if the effect depends on the location or the type of mutation. Toward this end, we have studied the effect of five nonsense mutations and two missense mutations on the expression of human .beta.-globin mRNA in a heterologous transfection system. In all cases studied, the presence of a translation termination codon correlates with a decrease in the steady-state level of mRNA. The data suggest that the metabolism of a mammalian mRNA is affected by the presence of a mutation that affects translation.