MLH1 Differential allelic expression in mutation carriers and controls

Germline defects in the MLH1 gene are associated with Lynch syndrome. A substantial proportion of these mutations leads to premature termination codons and can induce nonsense mediated decay (NMD) of the corresponding transcript. Resulting allelic expression differences represent a fast and inexpensive method to identify patients carrying MLH1 mutations. In patients and controls, we show that allelic expression imbalance (AEI) can be readily detected in RNA extracted from whole blood from patients carrying mutations expected to elicit NMD using mass spectrometry. Mutations closer to the 5' end of the gene tend to show smaller imbalances. AEI can also be detected in normal controls. Analysis of allelic expression in controls and individuals with mutations not expected to exhibit NMD revealed that MLH1 expression is influenced by sequence variation acting in cis. A maximum likelihood framework was used to identify two SNPs, rs1799977 (c.655G>A; p.I219V) and rs1800734 (c.-93 G>A) that are independently associated with expression. These influences are, however, small compared to the differences associated with pathological variants.