ASPA Sequence Based Mutation Analysis

From Bioinformatikpedia

Mutations

CM994594

Mutation: Tyr to Cys at position 231; we got it from dbSNP.

Tyrosine is an highly hydrophobic amino acid due to a benzene ring in its side chain. It occupies considerably more space than the thiol group that cysteine contains. What is more, they are quite hydrophilic and do form hydrogen bonds, both of which is not true of the benzene side chain of tyrosine.

This mutation is very common among Ashkenazi jews and causes Canavan's Disease.

CM940124

Mutation: Ala to Glu at position 305; we got it from dbSNP.

Alanine has a single carbon atom in its side chain, making it hydrophobic and very small. Glutamic acid is an entirely different animal, with a total of three carbon atoms in its side chain, the last of which being part of a carbon acid group. This makes it highly hydrophilic and also leads to a negative charge in the carboxyl group at physiological pH values.

This mutation is very common among Ashkenazi jews and causes Canavan's Disease.

RS104894553

Mutation: Arg to His at position 71; we got it from HGMD.

Arginine is hydrophilic, quite large, with a long side chain and three nitrogen atoms at the end, the chemistry of which gives it a positive charge at physiological pHs. Substituting it by Histidine takes away the charge and substitutes the outmost carbon atom and all of the nitrogen-containing groups with an imidazole group. This leads to a slight decrease in hydrophobicity and not much else.

This mutation is the most common disease-causing mutation among non-jews.

RS104894551

Mutation: Glu to Gly at position 24; we got it from HGMD.

Glutamic acid contains a carboxyl group and carries a negative charge at physiological pHs. Glycine doesn't have anything in the way of a proper side chain, with a hydrogen atom taking its place instead. While glutamic acid is quite hydrophilic, glycine has the chemical properties of the amino acid backbone, which is fairly aliphatic.

RS104894548

Mutation: Cys to Arg at position 152; we got it from HGMD.

Cysteine contains a thiol group, which is hydrophilic and forms hydrogen bridges; Arginine is negatively charged at physiological pHs and hydrophilic and occupies much more space than cysteine.

RS80099330

Mutation: Met to Thr at position 82; we got it from HGMD.

Methionine is a hydrophobic amino acid; Threonine, by contrast, contains an hydroxyl group in the middle of its side chain, which makes it hydrophilic and polar.

CM063847

Mutation: Thr to Ile at position 166; we got it from dbSNP.

The hydrophilic and polar threonine structurally differs not very much from Isoleucine; for the hydroxyl group, a C atom is substituted, and the side chain elongated by another C.

CM990193

Mutation: Pro to His at position 183; we got it from dbSNP.

Proline is hydrophobic and contains a hetero-pentacyclus with one thiol group. Histidin contains such a cyclus, too, but with another nitrogen atom. It carries a positive charge and is hydrophilic.

CM990195

Mutation: Met to Arg at position 195; we got it from dbSNP.

Methionine is hydrophobic; Arginine is positively charged and hydrophilic and more spacious than methionine.

CM055097

Mutation: Lys to Glu at position 213; we got it from dbSNP.

Lysine contains a positively charged nitrogen atom part of an ammonium group; Glutamic acid carries a negative charge on a carboxyl group. Both are hydrophilic and of comparable size.

PSSM

Mutated / Wildtype

          A  R  N  D  C  Q  E  G  H  I  L  K  M  F  P  S  T  W  Y  V   A   R   N   D   C   Q   E   G   H   I   L   K   M   F   P   S   T   W   Y   V
  24 E   -4 -3 -3 -1 -7  0  8 -5 -3 -6 -6 -2 -5 -6 -4 -3 -4 -6 -5 -6    0   0   0   0   0   1  99   0   0   0   0   0   0   0   0   0   0   0   0   0  2.24 1.67
  71 R   -4  8 -3 -2 -6 -2 -3 -5 -1 -5 -4 -1  1 -5 -5 -3 -4 -5 -4 -5    0  88   0   3   0   0   0   0   1   0   0   0   5   0   0   0   0   0   0   0  1.96 1.46
  82 M    1 -2  1  2 -1  0 -1  1  0 -1 -2 -1  2 -3  1 -1  2 -3 -2 -1   10   2   6  10   1   4   4  12   3   4   4   3   5   1   6   5  14   0   2   5  0.15 1.53
 152 C   -2 -3 -1  1  3 -2 -2 -3 -2  3 -1 -4  2 -2 -2 -3 -2 -5 -1  5    2   2   3   8   6   2   2   2   1  16   3   1   4   1   3   2   2   0   2  39  0.64 2.02
 166 T    2 -2 -1 -1 -2 -2 -1 -1 -1 -3 -2 -4 -2  3 -2  2  3  1  3 -1   15   2   2   3   1   1   5   5   1   1   4   1   1  12   2  15  16   2  10   3  0.34 2.09
 183 P    0 -1  0 -1  1  0 -1  1  0 -4 -1 -1  0 -1  4  0 -1  4  0 -2    9   3   4   4   3   4   3  12   3   0   6   4   3   3  17   6   3   6   3   3  0.26 1.80
 195 M    1 -1 -4 -1  2 -1 -1  1  1  1  0 -4  3  1 -5 -1  2 -5  0  1   12   3   0   3   5   3   3   9   4   9   7   0   9   5   0   4  11   0   4   8  0.21 1.85
 213 K   -1  1  0  2  1  0  0 -1  1 -1 -1  0  1  0  1 -1  0 -5  0 -1    6   7   4  10   3   5   5   4   3   4   8   7   3   4   8   5   6   0   3   5  0.07 2.08
 231 Y    0  0 -4 -4 -2 -2 -2 -3 -4 -1  0  2  1  2 -4 -1 -2  6  4 -1   10   6   0   1   1   1   3   2   0   3   8  14   4   8   1   4   2  13  15   5  0.52 1.95
 305 A    3 -4 -5 -5  2 -4 -4 -4 -5  1  2 -4 -2  0 -4 -2 -3 -5 -3  5   24   0   0   0   4   0   0   0   0   7  17   0   0   3   0   3   0   0   0  41  0.71 1.09

Secondary Structure

ASPA: MTSCHIAEEHIQKVAIFGGTHGNELTGVFLVKHWLENGAEIQRTGLEVKPFITNPRAVKKCTRYID
MUT:  MTSCHIAEEHIQKVAIFGGTHGNGLTGVFLVKHWLENGAEIQRTGLEVKPFITNPRAVKKCTRYID
SS:   ------------EEEEEEEE------HHHHHHHHHH---------EEEEEEEE-HHHHHH-----H

ASPA: CDLNRIFDLENLGKKMSEDLPYEVRRAQEINHLFGPKDSEDSYDIIFDLHNTTSNMGCTLILEDSR
MUT:  CDLNHIFDLENLGKKTSEDLPYEVRRAQEINHLFGPKDSEDSYDIIFDLHNTTSNMGCTLILEDSR
SS:   ---------------------HHHHHHHHHHHHHH-------EEEEEE-----------EEEE---

ASPA: NNFLIQMFHYIKTSLAPLPCYVYLIEHPSLKYATTRSIAKYPVGIEVGPQPQGVLRADILDQMRKM
MUT:  NNFLIQMFHYIKTSLAPLPRYVYLIEHPSLKYAITRSIAKYPVGIEVGPQHQGVLRADILDQRRKM
SS:   -HHHHHHHHHHHH------EEEEEE---------HHEE----EEEEE---------HHHHHHHHHH

ASPA: IKHALDFIHHFNEGKEFPPCAIEVYKIIEKVDYPRDENGEIAAIIHPNLQDQDWKPLHPGDPMFLT
MUT:  IKHALDFIHHFNEGEEFPPCAIEVYKIIEKVDCPRDENGEIAAIIHPNLQDQDWKPLHPGDPMFLT
SS:   HHHHHHHHHHH----------EEEEEEEEEE----------EEEE----------------HHE--

ASPA: LDGKTIPLGGDCTVYPVFVNEAAYYEKKEAFAKTTKLTLNAKSIRCCLH
MUT:  LDGKTIPLGGDCTVYPVFVNEEAYYEKKEAFAKTTKLTLNAKSIRCCLH
SS:   ----EEEE----EEEEEEE-----HHH-HHHHHHHHEEE-----EEEE-

Multiple Sequence Alignment

We calculated our MSA using T-Coffee

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Table of Results

Mutation Pos. Blosum Score Worst? PAM250 Score Worst? PAM1 Score Worst? PSSP Mutated Wildtype MSA Mutated Wildtype Polyphen Prediction Score Sift Prediction Score Median Conservation SNAP Prediction Reliability Exp. Accuracy
Tyr->Cys 231 -2 no -0.5 no 3 no -2 15 0.0% 73.7% damaging 1.0 affect 0.00 3.02 Non-neutral 5 87%
Ala->Glu 305 -1 no 0 no 17 no -4 3 0.0% 68.8% damaging 1.0 affect 0.02 3.14 Non-neutral 3 78%
Arg->His 71 0 no 0.6 no 8 no -1 8 0.0% 100.0% damaging 1.0 affect 0.01 3.02 Non-neutral 6 93%
Glu->Gly 24 -2 no -0.8 no 7 no -5 8 0.0% 100.0% damaging 1.0 affect 0.00 3.02 Non-neutral 7 96%
Cys->Arg 152 -3 yes -2.2 yes 1 no -3 3 0.0% 100.0% damaging 0.999 affect 0.01 3.07 Non-neutral 6 93%
Met->Thr 82 -1 no -0.6 no 6 no 14 2 0.0% 57.9% benign 0.0 tolerated 0.16 3.02 Non-neutral 0 58%
Thr->Ile 166 -1 no -0.6 no 7 no 1 16 0.0% 73.7% damaging 1.0 affect 0.04 3.07 Non-neutral 2 70%
Pro->His 183 -2 no -1.1 no 3 no 0 4 5.3% 94.7% damaging 1.0 affect 0.00 3.07 Non-neutral 6 93%
Met->Arg 195 -1 no -1.7 no 4 no -1 3 0.0% 94.7% damaging 0.991 affect 0.03 3.04 Non-neutral 5 87%
Lys->Glu 213 1 no 1.2 no 4 no 0 0 0.0% 73.7% benign 0.014 tolerated 0.83 3.02 Neutral 3 78%