Single Base-Pair Substitutions at the Translation Initiation Sites of Human Genes as a Cause of Inherited Disease

A total of 405 unique single base-pair substitutions, located within the ATG translation initiation codons (TICs) of 255 different genes, and reported to cause human genetic disease, were retrieved from the Human Gene Mutation Database (HGMD). Although these lesions comprised only 0.7% of coding sequence mutations in HGMD, they nevertheless were 3.4-fold over-represented as compared to other missense mutations. The distance between a TIC and the next downstream in-frame ATG codon was significantly greater for genes harboring TIC mutations than for the remainder of genes in HGMD (control genes). This suggests that the absence of an alternative ATG codon in the vicinity of a TIC increases the likelihood that a given TIC mutation will come to clinical attention. An additional 42 single base-pair substitutions in 37 different genes were identified in the vicinity of TICs (positions -6 to +4, comprising the so-called "Kozak consensus sequence"). These substitutions were not evenly distributed, being significantly more abundant at position +4. Finally, contrary to our initial expectation, the match between the original TIC and the Kozak consensus sequence was significantly better (rather than worse) for genes harboring TIC mutations than for the HGMD control genes. Hum Mutat 32:1137-1143, 2011. (C) 2011 Wiley-Liss, Inc.