A meta-analysis of nonsense mutations causing human genetic disease

Abstract

Nonsense mutations account for approximately 11% of all described gene lesions causing human inherited disease and approximately 20% of disease-associated single-basepair substitutions affecting gene coding regions. Pathological nonsense mutations resulting in TGA (38.5%), TAG (40.4%), and TAA (21.1%) occur in different proportions to naturally occurring stop codons. Of the 23 different nucleotide substitutions giving rise to nonsense mutations, the most frequent are CGA --> TGA (21%; resulting from methylation-mediated deamination) and CAG --> TAG (19%). The differing nonsense mutation frequencies are largely explicable in terms of variable nucleotide substitution rates such that it is unnecessary to invoke differential translational termination efficiency or differential codon usage. Some genes are characterized by numerous nonsense mutations but relatively few if any missense mutations (e.g., CHM) whereas other genes exhibit many missense mutations but few if any nonsense mutations (e.g., PSEN1). Genes in the latter category have a tendency to encode proteins characterized by multimer formation. Consistent with the operation of a clinical selection bias, genes exhibiting an excess of nonsense mutations are also likely to display an excess of frameshift mutations. Tumor suppressor (TS) genes exhibit a disproportionate number of nonsense mutations while most mutations in oncogenes are missense. A total of 12% of somatic nonsense mutations in TS genes were found to occur recurrently in the hypermutable CpG dinucleotide. In a comparison of somatic and germline mutational spectra for 17 TS genes, approximately 43% of somatic nonsense mutations had counterparts in the germline (rising to 98% for CpG mutations). Finally, the proportion of disease-causing nonsense mutations predicted to elicit nonsense-mediated mRNA decay (NMD) is significantly higher (P=1.56 x 10(-9)) than among nonobserved (potential) nonsense mutations, implying that nonsense mutations that elicit NMD are more likely to come to clinical attention.

Nonsense-mediated mRNA decay in humans at a glance

“…One-third of inherited human diseases are due to PTCs that are introduced by nonsense mutations, frameshift mutations or splicing errors (Frischmeyer and Dietz, 1999;Linde and Kerem, 2008), and nonsense mutations account for ∼20% of the around 43,000 disease-associated single-base pair substitutions (Mort et al, 2008) and for 5 to 70% of genetic disorders (Lee and Dougherty, 2012). NMD functions to eliminate transcripts that harbor nonsense codons that would otherwise result in the production of truncated proteins that have the potential to increase disease severity.…”

“…NMD accelerates the degradation of aberrant mRNAs harboring a premature termination codon (PTC) and, in this capacity, is estimated to downregulate one-third of disease-causing mRNAs (Frischmeyer and Dietz, 1999;Mort et al, 2008). In humans, PTCs were first reported to reduce mRNA abundance in 1979 (Chang et al, 1979) and, shortly after, to reduce mRNA stability (Maquat et al, 1981) through studies of the β o -thalassemias.…”

Abundance and length of simple repeats in vertebrate genomes are determined by their structural properties

“…For example, >16,000 tracts of mononucleotides comprised of Ն30 As or Ts are present in the human genome, but only seven analogous tracts of Gs or Cs are found (Bacolla et al 2006). 5Ј CpG 3Ј -(CpG)-containing repeats are generally rare, suggesting that cytosine methylation and subsequent deamination leading to T:A transitions from 5m C:G base pairs (Walsh and Xu 2006), a frequent cause of human gene mutation (Mort et al 2008), may have been involved (Kelkar et al 2008). However, because the rates of cytosine methylation (Bacolla et al 2001) and 5m C deamination (Lindahl and Nyberg 1974;Frederico et al 1993) decrease with increasing DNA stability, CpG-containing triNR and tetraNR are expected to display varying transition rates according to their C+G content (Elango et al 2008).…”

Structural and phylogenetic comparison of napsin genes: The duplication, loss of function and human-specific pseudogenization of napsin B

“…The loss of function due to nonsense mutations has been implicated as disease causing in ~15%-30% of monogenic inherited diseases (Mort et al, 2008). It was previously proposed that, in some cases, pseudogenization could confer a selective advantage.…”