Nonsensemutationer

Nonsensemutationer, or nonsense mutations, are single-nucleotide changes in a gene’s coding sequence that convert a sense codon into a termination codon. The three stop codons in most systems are UAA, UAG, and UGA. When a premature stop codon is introduced in an mRNA, translation usually terminates early, producing a truncated protein that often lacks essential domains and is typically nonfunctional. Such mutations can have severe phenotypic consequences.

Most premature termination codons trigger nonsense-mediated decay, a cellular quality-control mechanism that degrades mRNAs containing PTCs more than about 50–55 nucleotides upstream of the final exon–exon junction. This lowers mRNA levels and reduces protein production. In cases where NMD is ineffective, truncated proteins may accumulate and exert dominant-negative effects or residual activity, depending on the gene and the truncation point.

Nonsense mutations underlie a range of inherited diseases, including Duchenne muscular dystrophy, cystic fibrosis, beta-thalassemia, and several forms of retinitis pigmentosa. They also contribute to tumor-suppressor gene inactivation in cancer. Therapeutic approaches aim to restore full-length protein by promoting translational read-through of stop codons with drugs such as ataluren or certain aminoglycosides, or by modulating NMD or applying gene therapy strategies. The effectiveness of these methods is gene- and context-dependent.

Detection and study rely on DNA sequencing to identify the mutation, followed by RNA and protein analyses to assess NMD activation and protein production. Databases such as ClinVar and disease-gene resources catalog nonsense mutations and their clinical significance, aiding diagnosis and research.

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