Characterization of Disease-Associated Mutations in Human Transmembrane Proteins

Abstract

Transmembrane protein coding genes are commonly associated with human diseases. We characterized disease causing mutations and natural polymorphisms in transmembrane proteins by mapping missense genetic variations from the UniProt database on the transmembrane protein topology listed in the Human Transmembrane Proteome database. We found characteristic differences in the spectrum of amino acid changes within transmembrane regions: in the case of disease associated mutations the non-polar to non-polar and non-polar to charged amino acid changes are equally frequent. In contrast, in the case of natural polymorphisms non-polar to charged amino acid changes are rare while non-polar to non-polar changes are common. The majority of disease associated mutations result in glycine to arginine and leucine to proline substitutions. Mutations to positively charged amino acids are more common in the center of the lipid bilayer, where they cause more severe structural and functional anomalies. Our analysis contributes to the better understanding of the effect of disease associated mutations in transmembrane proteins, which can help prioritize genetic variations in personal genomic investigations.

Fig 1. Distribution of genetic variations across transmembrane proteins.

Blue bars represent proteins from the Human Transmembrane Proteome database, red bars represent TMPs containing disease-associated mutation(s), green bars represent TMPs containing polymorphism(s). TMPs with more than 12 TM segments were not included in the figure because of the low number of those proteins.

Fig 2. Substitution frequency within distinct regions of the TMP(s).

Blue bars represent disease-associated mutations, red bars represent polymorphisms. Values were counted within the distinct regions of the proteins, and normalized to the length of each segment.

Fig 3. Relative frequencies of mutations in the membrane regions of transmembrane proteins.

The distance was measured in the sequence from the most central amino acid in the transmembrane region and was normalized by the length (in residue) of the TM regions. Blue bars represent naturally occurring arginine residues within the TM region. Red bars represent the glycine to arginine disease-associated mutations within the TM region. Green bars represent all polymorphisms found within the TM region.

Fig 4. Distribution of TMPs containing naturally occurring arginine amino acids and disease associated glycine to arginine mutations within the TM region.

Blue bars represent those proteins which contain arginine residue(s) in the TM segment. Red bars represent those proteins which contain disease-associated glycine to arginine mutation(s) within the TM segment.

Fig 5. Distribution of relative frequencies of mutations along the z-axis.

The relative frequencies of disease causing mutations (blue) and polymorphisms (red) are shown along the z-axis See Materials and Methods for details.