Table 2.
Effect of non-synonymous amino acid changes on the biophysical properties of ASB10 protein and on structure stability
| Mutations | Loss of positive charge | Loss of negative charge | Charge unaffected, polarity affected | Charge and polarity unaffected | Functional effect | Patients (n = 1172) | Controls (n = 461) | Phenotype |
|---|---|---|---|---|---|---|---|---|
| Pro19Ser | X | Impaired | 6 | 0 | 6 POAG | |||
| Arg32Ser | XX | Impaired | 1 | 0 | 1 POAG | |||
| Arg39Gln | XX | Impaired | 1 | 0 | 1 POAG | |||
| Thr48Ser* | X | Non-impaired | 1 | 0 | 1 NTG | |||
| Gly65Glu* | X | Impaired | 1 | 0 | 1 POAG | |||
| Val67Met* | X | Non-impaired | 1 | 0 | 1 POAG | |||
| Arg72His* | X | Impaired | 10 | 1 | 1 JOAG, 5 NTG, 4 POAG | |||
| Asp88Val* | XX | Impaired | 1 | 1 | 1 POAG | |||
| Asp91Tyr* | XX | Impaired | 0 | 1 | ||||
| Arg94Gln* | XX | Impaired | 1 | 0 | 1 JOAG | |||
| Asp97Glu* | X | Non-impaired | 1 | 0 | 1 NTG | |||
| Ala157Val | X | Non-impaired | 0 | 1 | ||||
| Arg168Cys | XX | Impaired | 1 | 0 | 1 POAG | |||
| Arg174Trp | XX | Impaired | 3 | 1 | 3 POAG | |||
| Ala182Val | XS | Impaired | 1 | 0 | 1 POAG | |||
| Val192Leu | XS | Impaired | 7 | 0 | 4 POAG, 3 NTG | |||
| Arg222Gly | XX | Impaired | 12 | 4 | 5 POAG, 7 NTG | |||
| Arg257His | X | Impaired | 1 | 0 | 1 POAG | |||
| Gln280Leu | XS | Impaired | 1 | 0 | 1 NTG | |||
| Arg289Cys | XX | Impaired | 9 | 2 | 5 POAG, 4 NTG | |||
| Ala305Thr | XS | Impaired | 1 | 0 | 1 NTG | |||
| Thr314Met | X | Impaired | 1 | 1 | 1 NTG | |||
| His317Gln | X | Impaired | 1 | 0 | 1 POAG | |||
| His341Tyr | X | Impaired | 1 | 0 | 1 NTG | |||
| Arg345His | X | Impaired | 2 | 0 | 1 POAG, 1 NTG | |||
| Ser425Gly | X | Impaired | 1 | 0 | 1 POAG | |||
| Arg438Cys | XX | Impaired | 4 | 1 | 2 POAG, 2 NTG | |||
| Total | 70 | 13 | ||||||
| Impaired total | 67 | 12 |
Mutations that potentially lead to the loss of a positively or negatively charged residue are marked by ‘XX’ and are listed in the first and second columns, respectively. As histidine is only partially charged at physiological pH, mutations involving this residue are marked by a single ‘X’ to highlight the milder effect. The fourth column lists mutations that have no effect on either charge or polarity of ASB10. Mutations located in a region of known three-dimensional structure were evaluated for their effect on protein stability. Mutations which are predicted to significantly decrease the protein stability due to steric clashes (Fig. 5) are marked by a superscript ‘S’. ASB10 ref. seq. is NM_080871.3 and NP_543147.2 (isoform 3); if marked by *, then it is NM_001142459.1 and NP_001135931.2 (isoform 1). In this analysis, we excluded the nonsense change (p.Cys173X) and the two common variants (p.Arg357Cys and p.Pro387Thr).