Although nonsense-mediated mRNA decay reduces nonsense codons, mutations can occur that lead to various health problems and diseases in humans. A dominant-negative or deleterious gain-of-function mutation can occur if premature terminating (nonsense) codons are translated. NMD is becoming increasingly evident in the way it modifies phenotypic consequences because of the broad way it controls gene expression. For instance, the blood disorder Beta thalassemia is inherited and caused by mutations within the upstream region of the β-globin gene. An individual carrying only one affected allele will have no or extremely low levels of the mutant β-globin mRNA. An even more severe form of the disease can occur called thalassemia intermedia or ‘inclusion body’ thalassemia. Instead of decreased mRNA levels, a mutant transcript produces truncated β chains, which in turn leads to a clinical phenotype in the heterozygote.
Nonsense-mediated decay mutations can also contribute to Marfan syndrome. This disorder is caused by mutations in the fibrillin 1 (FBN1) gene and is resulted from a dominant negative interaction between mutant and wild-type fibrillin-1 gene.