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NMD and Human Disease

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We discuss in this chapter how nonsense-mediated mRNA decay (NMD) affects the expression of human genetic diseases resulting from premature termination codons (PTCs) by considering how NMD alters disease phenotype. NMD may exert a beneficial, neutral, or harmful effect, depending on the location of the PTC in the transcript and the properties of the truncated protein. In the case of many PTCs, the resulting truncated protein might be nonfunctional and could be degraded without harmful effects. In these instances, NMD probably does not significantly influence phenotype. In other cases, NMD can prevent expression of potentially dominant negative proteins. Therefore, NMD can sometimes exert a protective effect that benefits heterozygous carriers of PTCs. NMD can also contribute to a disease phenotype when it inhibits expression of partially functional proteins. Therapies that could affect gene expression in such cases are under development and may, in the future, provide avenues for effective clinical treatment of diseases that involve NMD.

“NMD-Neutral” PTCs

In general, whether NMD alters the phenotype of a disease depends on both the affected gene and the location of the disease-causing PTC. PTCs upstream of the so-called “NMD boundary,” which is located 50 to 55 bases 5' of the last exon-exon junction, generally trigger NMD of the affected transcript. In contrast, PTCs 3' of this boundary generally escape detection by the NMD machinery, leading to transcript survival. Perhaps surprisingly, it is likely that NMD often has no discernible effect on disease phenotype, since in the absence of NMD many PTCs would probably lead to expression of inactive peptides rather than dominant-negative proteins. Although it might be expected that many PTCs would fall into this “NMD-neutral” category, experimental data are lacking to demonstrate that particular PTCs lead to an identical phenotype in both the presence and absence of NMD. Such “neutral” PTCs will therefore not be discussed further.

NMD-Mediated Protection of Heterozygotes: The Example of β-Thalassemia

NMD may be expected to be beneficial when it inhibits expression of truncated proteins that could exert deleterious effects. The prototypical genetic condition illustrating the protective effects of NMD is β-thalassemia, which is a disorder of hemoglobin production. Normal hemoglobin, which is necessary for oxygen transport, is a tetramer composed of two α-globin and two β-globin subunits. The common recessive form of β-thalassemia occurs in homozygotes who possess NMD-competent PTCs in both copies of the β-globin gene. The resulting defective β-globin mRNA is degraded by NMD. Free α-globin, which is toxic, is then present in excess and is degraded proteolytically.2 Therefore, the quantity of tetrameric hemoglobin is insufficient, causing severe anemia in affected persons. In comparison, heterozygous carriers of a single NMD-competent PTC generally produce enough β-globin from the normal allele to maintain sufficient amounts of tetrameric hemoglobin, and they are clinically healthy. Rare forms of dominant β-thalassemia, in contrast, are caused by NMD-incompetent PTCs within the last exon of the β-globin gene. These PTCs give rise to a large amount of truncated β-globin that cannot be sufficiently degraded and precipitates in toxic inclusion bodies.3 The remarkable difference between healthy heterozygotes possessing NMD-competent PTCs and anemic heterozygotes possessing NMD-incompetent PTCs indicates that NMD protects many healthy heterozygotes from manifesting clinical disease4 (Fig. 1).

Figure 1. Position-dependent effects of nonsense mutations of NMD correlate with inheritance pattern and clinical severity of disease.

Figure 1

Position-dependent effects of nonsense mutations of NMD correlate with inheritance pattern and clinical severity of disease. Human β-globin mRNAs that contain PTCs within their 5' portion are generally targeted by NMD, protecting heterozygotes (more...)

Although β-thalassemia is the only genetic condition so far in which the protective effect of NMD has been thoroughly investigated by experiment, a similar protective role of NMD for heterozygotes with NMD-competent PTCs can be reasonably postulated from similar genotype-phenotype relationships in a number of other diseases (Table 1). These include:

Table 1. Genetic conditions in which NMD can modulate phenotype.

Table 1

Genetic conditions in which NMD can modulate phenotype.

  • Dominantly and recessively inherited susceptibility to mycobacterial infections caused by mutations in the IFNGR1 gene.5,6 The recessive form of this condition is often fatal, with patients succumbing to disseminated mycobacterial infections at a young age. This form is caused by PTCs that are probably NMD-competent, since no IFNGR protein was found in a patient with recessive disease. Heterozygous carriers of these PTCs are healthy. The dominant form of the disease arises from PTCs that are predicted to be NMD-incompetent. This form results in production of a truncated IFNGR receptor, as may be expected for a transcript that survives NMD. Heterozygotes manifest increased susceptibility to mycobacterial infection, although such infections are generally not as severe as in the recessive case.
  • Brachydactyly type B (see ref. 7), which is a dominant condition involving malformed hands and feet, and Robinow syndrome, which is recessive and characterized by more severe skeletal malformation. Both diseases are caused by mutations in the ROR2 gene. Brachydactyly type B is caused by PTCs that are expected to be NMD-incompetent. Robinow syndrome is characterized by PTCs that should be NMD-competent, and heterozygous carriers are unaffected.
  • Dominant and recessive von Willebrand disease,8 which are disorders of blood clotting. PTCs that should be NMD competent lead to severe disease, but only in a pattern of recessive inheritance. In contrast, a mutation that removes the physiological stop codon and results in a new stop codon downstream creates a mutated transcript that should not be an NMD substrate and results in dominant disease.
  • Dominant and recessive factor X deficiency,9 which is another disorder of blood clotting. Factor X deficiency is usually transmitted in an autosomal recessive pattern so that heterozygous carriers are healthy. Among the causative mutations, some generate NMD-competent PTCs. A splice site mutation that results in a PTC that should be NMD-incompetent, however, leads to moderate disease in heterozygotes.
  • Retinal degeneration.10-12 PTCs in the 3´ end of the CRX gene, downstream of the NMD boundary, lead to disease in heterozygotes. In contrast, a PTC upstream of the NMD boundary was found in a healthy heterozygote. Mutations in the rhodopsin gene follow a similar pattern.

A somewhat different example that also demonstrates the protective effect of NMD is provided by the SOX10 gene. In this case, both NMD-competent and NMD-incompetent PTCs give rise to disease. The NMD-competent PTCs appear to cause simple haploinsufficiency, and they result in hereditary neurosensory deafness and intestinal obstruction. However, the NMD-incompetent PTCs results in the production of a dominantly acting truncated protein, which causes a more severe syndrome that includes central and peripheral demyelination.13

Taken in sum, these genetic conditions provide considerable evidence that NMD protects heterozygous carriers of PTCs from expressing dominantly acting deleterious truncated proteins. It is also noteworthy that in many of these conditions, the most severe disease is evident in patients harboring two autosomal recessive mutations. These patients are usually typified by complete or near-complete protein deficiency. Patients harboring dominant mutations, in contrast, usually retain some protein function, which tends to ameliorate the disease phenotype.

NMD in Acquired Genetic Conditions1

Mutations in tumor-suppressor genes are common steps in the development and progression of cancer. As with inherited genetic conditions, NMD appears to provide protection against expression of mutated, truncated tumor-suppressor peptides. For example, NMD has been shown to degrade PTC-containing transcripts arising from the BRCA1 gene.14 PTC-containing mRNAs from the TP53 and Wilms tumor (WT1) loci15-19 are also reduced in abundance compared to wildtype or missense mutated transcripts, presumably due to the action of NMD.

Evidence that NMD protects against dominant truncated forms of these tumor-suppressor proteins derives from experiments in which intronless cDNA constructs encoding unspliced mRNAs that are NMD-incompetent are expressed in cell lines or animals. The resulting C-terminally truncated proteins exert dominant detrimental effects, such as increased chemoresistance, decreased apoptosis, increased tumorigenicity,20-22 interference with transcription-activating ability, and mislocalization of the corresponding cellular tumor suppressor protein23,24 (Table 2). These studies indicate that if abnormal transcripts containing PTCs were not degraded by NMD, clinically recessive tumor-suppressor mutations could instead result in dominant disease due to the synthesis of truncated, dominantly acting oncoproteins. NMD may thus protect heterozygous carriers of PTC-mutated tumor-suppressor genes from developing cancer, at least for as long as the other tumor-suppressor allele remains intact.

Table 2. Effect of NMD on expression of tumor-suppressor genes.

Table 2

Effect of NMD on expression of tumor-suppressor genes.

NMD may also affect expression of certain tumor-suppressor genes by modulating the quantity of splice variants produced by these genes, although this hypothesis remains somewhat speculative. For example, the TP53 gene produces a splice variant that contains a PTC at low levels in normal tissues.25 In contrast, a much larger amount of this splice variant —accounting for approximately half of all TP53 transcripts—was found in a leukemic cell line.26 Although a causal relationship has not yet been established, large amounts of the splice variant could potentially contribute to leukemogenesis, which would be prevented under normal conditions by NMD-induced degradation of the variant.

Transcripts from the WT1 gene also undergo alternative splicing to produce two major splice forms. The more abundant splice form (+KTS) encodes three additional amino acids at the 3' end of the penultimate exon, while the less abundant splice form (-KTS) lacks these residues. Interestingly, a mutation found in acute myelogenous leukaemia,27 Wilms tumor28 and Frasier syndrome (male pseudohermaphroditism and progressive glomerulopathy)29 is also located within the penultimate exon of the WT1 gene. This mutation introduces an NMD-competent PTC, but only for the +KTS form. In contrast, for the -KTS form, the PTC is within the terminal 50 bases of the penultimate exon. Therefore, -KTS transcripts probably escape NMD and are translated to produce a truncated protein (Fig. 2). NMD could thus limit expression of the primary transcript. This is important because, in general, Frasier syndrome is attributable to mutations that selectively reduce the abundance of the +KTS isoform.30,31 Therefore, Frasier syndrome in individuals carrying this particular PTC mutation could be caused by NMD-induced degradation of the +KTS isoform. In addition, the truncated form of the minor splice variant might act in a dominant fashion to promote tumorigenesis.

Figure 2. Different fates of PTC-containing splice variants derived from the WT1 gene.

Figure 2

Different fates of PTC-containing splice variants derived from the WT1 gene. The penultimate exon of the +KTS splice variant (lower) encodes an extra three amino acids, whereas the -KTS variant (upper) lacks these amino acids. Therefore, NMD should result (more...)

Medical Therapies for PTC-Related Disease

In contrast to its role in preventing dominant disease, NMD can also eliminate mRNAs that would otherwise result in the production of partly or fully functional truncated protein, thereby contributing to the protein deficiency that is the hallmark of many recessive genetic conditions. In such instances, interventions to prevent degradation of transcripts containing PTCs may be therapeutically useful. Drug therapy with these aims is the subject of Chapter 10 in this book and therefore will be discussed only briefly here.

At this time, the therapeutic approach that is closest to clinical applicability is the use of aminoglycoside antibiotics that allow read-through of nonsense codons. These drugs bind to the decoding center of the ribosome32 and decrease the accuracy requirements for codon-anticodon pairing, thereby resulting in incorporation of an amino acid into the polypeptide chain instead of chain termination. Thus, full-length, albeit missense-mutated, proteins are synthesized. Aminoglycosides have been used to treat Duchenne muscular dystrophy, Hurler syndrome, X-linked nephrogenic diabetes insipidus, ataxia-telangiectsia, and cystinosis, resulting in some functional improvement in cell lines33-39 and animal models.36,40 Some trials of aminoglycoside therapy also have been carried out in humans with PTC-associated diseases. Promising results have been obtained in a controlled clinical trial for cystic fibrosis, in which full-length CFTR protein was detected in nasal epithelial cells of two treated individuals.41 In contrast, clinical studies of individuals with muscular dystrophy have not shown functional improvement.42,43 Overall, although early results indicate that aminoglycoside treatment may have potential applicability, a therapeutic benefit has yet to be demonstrated. The effect of prolonged treatment with aminoglycosides is also a concern. First, there is the problem of toxicity. Second, there is the issue of whether the general, long-term suppression of PTCs, which is accompanied by the suppression of physiologic termination codons and the potential for pseudogene transcript translation, will result in the build-up of abnormal proteins that could trigger other cellular problems.

Other approaches to modulating PTC-induced transcript degradation are also under investigation. One potential approach is to use antisense oligoribonucleotides to redirect splicing, thereby avoiding the production of PTCs in the first place. Initially described as a method for correcting the in vitro aberrant splicing of a disease-associated beta globin gene,44 this strategy employs antisense 2'-O-methylribonucleotides (2OMeAO) that hybridize to splice sites or branch point junctions of aberrantly spliced pre-mRNA, thereby restoring normal splicing in a significant fraction of molecules. This approach was modified for use with a disease-associated dystrophin transcript.45 In this case, the targeted PTC was located within an exon coding for a dispensable protein region. Antisense 2OMeAO that targeted splice sites flanking the PTC promoted in-frame skipping of the affected exon, effectively removing the PTC. Treatment of mdx mice with these antisense oligonucleotides resulted in low-level expression of shortened but functional dystrophin. In a further step toward the clinic, the efficiency of oligonucleotide delivery to tissues has been enhanced by the use of vehicles such as block copolymer.46 Before trials of 2OMeAO are feasible in humans, however, a systemic delivery method needs to be developed. As with all forms of gene therapy, the issues of transfection efficiency, potential immune responses, and side effects must be addressed. Unfortunately, this sort of treatment would be feasible only for mutations in which manipulation of splicing maintains in-frame translation, and—if exon skipping is the result—that does not remove essential protein regions or result in protein mis-folding. Therefore, this treatment will probably be limited to specific cases rather than provide a general therapy for PTC-associated diseases.

A further potential approach—although currently very far from realization—involves modulating NMD per se, rather than modulating recognition of PTCs. Down-regulating the central NMD protein Upf1 using RNA interference has been shown to inhibit NMD in cultured cells, and it might constitute a starting point for therapeutic developments. Additionally, some evidence exists to suggest that different individuals with identical genetic mutations may exhibit distinct phenotypic severities due to differences in the efficiency of NMD.47 Thus, identifying factors that regulate the efficiency of NMD could permit development of therapies that fine-tune NMD, potentially allowing more targeted interventions in patients with PTC-associated diseases.


NMD plays an important role in modulating the manifestation of hereditary and acquired genetic diseases, and a deepening understanding of NMD will augment the establishment of genotype-phenotype relationships in a number of conditions. The contribution of NMD to genetic diseases may be beneficial, neutral or harmful, depending on the specific PTC, its location, and the type of mutation that generates the PTC. Therefore, the potential role of NMD in disease must be appreciated when the functional effect of a mutation is considered. Therapies that target PTC-containing transcripts are under development, and continued research in this direction should help lead to viable strategies to treat PTC-associated diseases.


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