Task 8 (MSUD)
Contents
Results
Visualization of mutations
- Original residues and mutations in BCKDHA (1U5B chain A)
Original residues of BCKDHA are marked in red.
Mutant residues are marged in orange.
Selected mutations
Following are the selected mutations from HGMD and dbSNP. Changes in physicochemical properties, secondary structures, amino acid substitution scores, conservation and prediction results of different programs are also shown in the table:
| mutation | physicochemical changes | secondary structure | BLOSUM62 score | PAM250 score | PSSM conservation WT | PSSM conservation mutant | MSA conservation WT | MSA conservation mutant | SIFT | Polyphen2 | MutationTaster | SNAP | DB |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| P38H | small/fixed conformation/apolar to large/aromatic/polar | - | -2 | 0 | 31 | 0 | 0.29 | 0 | tolerated | benign | polymorphism | NA | dbSNP |
| M82L | sulfur-containing to aliphatic/branched | E | 2 | 4 | 12 | 59 | 0.36 | 0.01 | tolerated | benign | disease causing | NA | dbSNP |
| T151M | small/polar to apolar/sulfur-containing | - | -1 | -1 | 8 | 0 | 0.8 | 0 | tolerated | probably/possibly damaging | disease causing | NA | HGMD |
| A222T | apolar to polar | H | 0 | 1 | 64 | 4 | 0.38 | 0 | affect protein function | probably damaging | disease causing | NA | dbSNP |
| C264W | small/sulfur-containing to large/aromatic | E | -2 | -8 | 52 | 0 | 0.91 | 0 | affect protein function | probably/possibly damaging | disease causing | NA | HGMD |
| R265W | positively-charged to aromatic/larger | E | -3 | 2 | 12 | 0 | 0.36 | 0.38 | affect protein function | probably damaging | disease causing | NA | HGMD |
| R314Q | guanidin/large/positively-charged to amin | H | 1 | 1 | 23 | 0 | 0.35 | 0 | affect protein function | probably damaging | disease causing | NA | dbSNP |
| R346H | hydrophilic to hydrophobic/aromatic | - | 0 | 2 | 92 | 0 | 0.9 | 0 | affect protein function | probably damaging | disease causing | NA | HGMD |
| I361V | smaller | H | 3 | 4 | 64 | 10 | 0.89 | 0.01 | tolerated | benign/possibly damaging | disease causing | NA | dbSNP |
| Y413H | uncharged to positively-charged | - | 2 | 0 | 74 | 1 | 0.9 | 0 | affect protein function | probably damaging | disease causing | NA | HGMD |
SIFT
The following table shows the prediction of mutation effects by SIFT. 6 out of 10 mutations are predicted to affect protein function.
| mutation | prediction | score | median sequence conservation | sequences represented at position |
|---|---|---|---|---|
| P38H | tolerated | 0.16 | 3.16 | 17 |
| M82L | tolerated | 0.56 | 3.03 | 43 |
| T151M | tolerated | 0.05 | 3.03 | 46 |
| A222T | affect protein function | 0.04 | 3.03 | 46 |
| C264W | affect protein function | 0.00 | 3.03 | 46 |
| R265W | affect protein function | 0.00 | 3.03 | 46 |
| R314Q | affect protein function | 0.01 | 3.03 | 46 |
| R346H | affect protein function | 0.00 | 3.03 | 46 |
| I361V | tolerated | 0.12 | 3.03 | 46 |
| Y413H | affect protein function | 0.00 | 3.03 | 46 |
Polyphen2
The prediction resuls of Polyphen2 are shown in the following table. 7 out of 10 mutations are predicted to be probably damaging (at least for the trained set HumDiv). For the mutation T151M, this does not agree with the results of SIFT. But for this mutations the Polyphen scores are also the lowest of all mutations that are predicted to be damaging. So Polyphen sees an uncertainty for this mutation too, if it is damaging.
| HumDiv | HumVar | |||||||
|---|---|---|---|---|---|---|---|---|
| mutation | prediction | score | sensitivity | specificity | prediction | score | sensitivity | specificity |
| P38H | benign | 0.118 | 0.93 | 0.96 | benign | 0.042 | 0.93 | 0.62 |
| M82L | benign | 0.002 | 0.99 | 0.30 | benign | 0.006 | 0.97 | 0.45 |
| T151M | probably damaging | 0.963 | 0.78 | 0.95 | possibly damaging | 0.622 | 0.80 | 0.85 |
| A222T | probably damaging | 1.000 | 0.00 | 1.00 | probably damaging | 0.943 | 0.65 | 0.91 |
| C264W | probably damaging | 0.989 | 0.72 | 0.97 | possibly damaging | 0.887 | 0.71 | 0.89 |
| R265W | probably damaging | 1.000 | 0.00 | 1.00 | probably damaging | 1.000 | 0.00 | 1.00 |
| R314Q | probably damaging | 1.000 | 0.00 | 1.00 | probably damaging | 0.998 | 0.18 | 0.98 |
| R346H | probably damaging | 1.000 | 0.00 | 1.00 | probably damaging | 0.993 | 0.47 | 0.96 |
| I361V | benign | 0.386 | 0.90 | 0.89 | possibly damaging | 0.610 | 0.80 | 0.83 |
| Y413H | probably damaging | 1.000 | 0.00 | 1.0 | probably damaging | 0.999 | 0.09 | 0.99 |
MutationTaster
| mutation | prediction | mutation.score | prediction.probability |
|---|---|---|---|
| A222T | disease causing | 1.58 | 0.99 |
| C264W | disease causing | 5.86 | 0.99 |
| I361V | disease causing | 0.79 | 0.99 |
| M82L | disease causing | 0.41 | 0.99 |
| P38H | polymorphism | 2.1 | 0.99 |
| R265W | disease causing | 2.75 | 0.99 |
| R314Q | disease causing | 1.17 | 0.99 |
| R346H | disease causing | 0.79 | 0.99 |
| T151M | disease causing | 2.21 | 0.93 |
| Y413H | disease causing | 2.26 | 0.99 |
