Table 1. PAH mutations in PAH-deficient patients from Fujian province
cDNA Aberration
|
Protein effect or
trivial name
|
Gene Region
|
Type
|
Protein Domain
|
No. Of alleles
|
RF(Relative frequency)
(%)
|
c.158G>A
|
p.Arg53His
|
Exon 2
|
Missense
|
regulatory
|
33
|
18.03
|
c.721C>T
|
p.Arg241Cys
|
Exon 7
|
Missense
|
catalytic
|
27
|
14.75
|
c.728G>A
|
p.Arg243Gln
|
Exon 7
|
Missense
|
catalytic
|
14
|
7.65
|
c.1174T>A
|
p.Phe392Ile
|
Exon 11
|
Missense
|
catalytic
|
11
|
6.01
|
c.1197A>T
|
p.Val399=
|
Exon 11
|
Splice/Silence
|
catalytic
|
11
|
6.01
|
c.1223G>A
|
p.Arg408Gln
|
Exon 12
|
Missense
|
catalytic
|
9
|
4.92
|
c.331C>T
|
p.Arg111Ter
|
Exon 3
|
Nonsense
|
regulatory
|
9
|
4.92
|
c.611A>G
|
p.Ex6-96A>G
|
Exon 6
|
Splice
|
catalytic
|
8
|
4.37
|
c.913-7A>G
|
p.IVS8-7A>G
|
Intron 8
|
Splice
|
—
|
5
|
2.73
|
c.442-1G>A
|
p.IVS4-1G>A
|
Intron 4
|
Splice
|
—
|
5
|
2.73
|
c.1162G>A
|
p.Val388Met
|
Exon 11
|
Missense
|
catalytic
|
3
|
1.64
|
c.1238G>C
|
p.Arg413Pro
|
Exon 12
|
Missense
|
catalytic
|
3
|
1.64
|
c.722del
|
p.Arg241ProfsTer100
|
Exon 7
|
Frame shift
Deletion
|
catalytic
|
3
|
1.64
|
c.856G>A
|
p.Glu286Lys
|
Exon 8
|
Missense
|
catalytic
|
3
|
1.64
|
c.1199G>A
|
p.Arg400Lys
|
Exon 11
|
Missense
|
catalytic
|
2
|
1.09
|
c.1217T>G
|
p.Ile406Arg
|
Exon 11
|
Missense
|
catalytic
|
2
|
1.09
|
c.1256A>G
|
p.Gln419Arg
|
Exon 12
|
Missense
|
catalytic
|
2
|
1.09
|
c.464G>A
|
p.Arg155His
|
Exon 5
|
Missense
|
catalytic
|
2
|
1.09
|
c.526C>T
|
p.Arg176Ter
|
Exon 6
|
Nonsense
|
catalytic
|
2
|
1.09
|
c.755G>A
|
p.Arg252Gln
|
Exon 7
|
Missense
|
catalytic
|
2
|
1.09
|
c.782G>A
|
p.Arg261Gln
|
Exon 7
|
Missense
|
catalytic
|
2
|
1.09
|
c.842C>T
|
p.Pro281Leu
|
Exon 7
|
Missense
|
catalytic
|
2
|
1.09
|
c.935G>T
|
p.Gly312Val
|
Exon 9
|
Missense
|
catalytic
|
2
|
1.09
|
c.103A>G
|
p.Ile35Val
|
Exon 2
|
Missense
|
regulatory
|
1
|
0.055
|
c.1043T>C
|
p.Leu348Pro
|
Exon 10
|
Missense
|
catalytic
|
1
|
0.055
|
c.1057G>T
|
p.Glu353Ter
|
Exon 10
|
Nonsense
|
catalytic
|
1
|
0.055
|
c.1065+39G>T
|
p.IVS10+39G>T
|
Intron 10
|
Splice
|
—
|
1
|
0.055
|
c.1068C>A
|
p.Tyr356Ter
|
Exon 11
|
Nonsense
|
catalytic
|
1
|
0.055
|
c.1073T>G
|
p.Leu358Ter
|
Exon 11
|
Nonsense
|
catalytic
|
1
|
0.055
|
c.1138del
|
p.Thr380ArgfsTer20
|
Exon 11
|
Frame shift
Deletion
|
catalytic
|
1
|
0.055
|
c.168+1G>C
|
p.IVS2+1G>C
|
Intron 2
|
Splice
|
—
|
1
|
0.055
|
c.353T>G
|
p.Val118Gly
|
Exon 3
|
Nonsense
|
regulatory
|
1
|
0.055
|
c.473G>A
|
p.Arg158Gln
|
Exon 5
|
Missense
|
catalytic
|
1
|
0.055
|
c.60G>C
|
p.Gln20His
|
Exon 1
|
Missense
|
regulatory
|
1
|
0.055
|
c.722G>A
|
p.Arg241His
|
Exon 7
|
Missense
|
catalytic
|
1
|
0.055
|
c.730C>T
|
p.Pro244Ser
|
Exon 7
|
Missense
|
catalytic
|
1
|
0.055
|
c.740G>T
|
p.Gly247Val
|
Exon 7
|
Missense
|
catalytic
|
1
|
0.055
|
c.827T>A
|
p.Met276Lys
|
Exon 7
|
Missense
|
catalytic
|
1
|
0.055
|
c.838G>A
|
p.Glu280Lys
|
Exon 7
|
Missense
|
catalytic
|
1
|
0.055
|
c.842+2T>A
|
p.IVS7+2T>A
|
Intron 7
|
Splice
|
—
|
1
|
0.055
|
c.898G>T
|
p.Ala300Ser
|
Exon 8
|
Missense
|
catalytic
|
1
|
0.055
|
c.910C>A
|
p.Gln304Lys
|
Exon 8
|
Missense
|
catalytic
|
1
|
0.055
|
c.964G>A
|
p.Ala322Thr
|
Exon 9
|
Missense
|
catalytic
|
1
|
0.055
|
c.971T>A
|
p.Ile324Asn
|
Exon 10
|
Missense
|
catalytic
|
1
|
0.055
|
Table 2. Comparisons of the PAH mutation frequencies between PAHD from Fujian and other regions in China
cDNA Aberration
|
Protein effect or
trivial name
|
Fujian
(%)
|
Eastern China [3]
(%)
|
North China [5]
(%)
|
South China [2]
(%)
|
Northwest China [17]
(%)
|
Central China [18]
(%)
|
c.158G>A
|
p.Arg53His
|
18.03
|
4.34
|
4.7
|
15.2
|
|
5.37
|
c.721C>T
|
p.Arg241Cys
|
14.75
|
13.27
|
4.6
|
13.8
|
|
7.38
|
c.728G>A
|
p.Arg243Gln
|
7.65
|
22.19
|
17.7
|
17.2
|
14.00
|
16.11
|
c.1174T>A
|
p.Phe392Ile
|
6.01
|
1.79
|
|
|
|
6.04
|
c.1197A>T
|
p.Val399=
|
6.01
|
0.77
|
6.4
|
5.2
|
|
|
c.1223G>A
|
p.Arg408Gln
|
4.92
|
2.81
|
|
|
|
|
c.331C>T
|
p.Arg111Ter
|
4.92
|
5.36
|
4.4
|
|
2.95
|
|
c.611A>G
|
p.Ex6-96A>G
|
4.37
|
8.93
|
8.3
|
20.7
|
5.58
|
10.07
|
c.913-7A>G
|
p.IVS8-7A>G
|
2.73
|
0.77
|
|
|
|
|
c.442-1G>A
|
p.IVS4-1G>A
|
2.73
|
5.61
|
3.4
|
5.2
|
4.32
|
|
c.1238G>C
|
p.Arg413Pro
|
1.64
|
|
4.6
|
6.9
|
4.74
|
|
c.722del
|
p.Arg241ProfsTer100
|
1.64
|
|
|
1.7
|
|
|
c.464G>A
|
p.Arg155His
|
1.09
|
|
|
3.4
|
|
|
c.1068C>A
|
p.Tyr356Ter
|
0.055
|
3.06
|
4.7
|
1.7
|
4.95
|
4.70
|
Table 3. PAH allele distribution in PAHD patients from Fujian province
cDNA Aberration
|
Protein effect or trivial name
|
Classical PKU
(n = 27)
|
Moderate PKU
(n =40)
|
MHP
(n = 116)
|
P value
|
No. of alleles
|
RF
( %)
|
No. of alleles
|
RF
(%)
|
No. of alleles
|
RF
( %)
|
|
c.158G>A
|
p.Arg53His
|
0
|
0.00
|
1
|
2.50
|
32
|
27.58
|
0.000#
|
c.721C>T
|
p.Arg241Cys
|
1
|
3.70
|
13
|
32.5
|
13
|
11.21
|
0.001#
|
c.728G>A
|
p.Arg243Gln
|
1
|
3.70
|
4
|
10.00
|
9
|
7.76
|
0.635
|
c.1174T>A
|
p.Phe392Ile
|
0
|
0.00
|
0
|
0.00
|
11
|
9.48
|
0.034#
|
c.1197A>T
|
p.Val399=
|
5
|
18.51
|
2
|
5.00
|
4
|
3.45
|
0.036#
|
c.1223G>A
|
p.Arg408Gln
|
1
|
3.70
|
4
|
10.00
|
4
|
3.45
|
0.243
|
c.331C>T
|
p.Arg111Ter
|
4
|
14.81
|
2
|
5.00
|
3
|
2.59
|
0.03#
|
c.611A>G
|
p.Ex6-96A>G
|
3
|
11.11
|
2
|
5.00
|
3
|
2.59
|
0.145
|
c.442-1G>A
|
p.IVS4-1G>A
|
0
|
0.00
|
0
|
0.00
|
5
|
4.31
|
0.098
|
c.913-7A>G
|
p.IVS8-7A>G
|
0
|
0.00
|
2
|
5.00
|
3
|
2.59
|
0.463
|
c.856G>A
|
p.Glu286Lys
|
0
|
0.00
|
2
|
5.00
|
1
|
0.86
|
0.158
|
c.722del
|
p.Arg241ProfsTer100
|
1
|
3.70
|
0
|
0.00
|
2
|
1.72
|
0.500
|
c.1256A>G
|
p.Gln419Arg
|
0
|
0.00
|
0
|
0.00
|
2
|
1.72
|
0.558
|
c.1199G>A
|
p.Arg400Lys
|
0
|
0.00
|
2
|
5.00
|
0
|
0.00
|
0.027#
|
c.1217T>G
|
p.Ile406Arg
|
1
|
3.70
|
0
|
0.00
|
1
|
0.86
|
0.333
|
c.464G>A
|
p.Arg155His
|
0
|
0.00
|
0
|
0.00
|
2
|
1.72
|
0.558
|
c.526C>T
|
p.Arg176Ter
|
1
|
0.00
|
0
|
0.00
|
2
|
1.72
|
0.558
|
c.755G>A
|
p.Arg252Gln
|
1
|
3.70
|
0
|
0.00
|
1
|
0.86
|
0.333
|
c.782G>A
|
p.Arg261Gln
|
0
|
0.00
|
0
|
0.00
|
2
|
1.72
|
0.558
|
c.842C>T
|
p.Pro281Leu
|
0
|
0.00
|
1
|
2.50
|
1
|
0.86
|
0.538
|
c.935G>T
|
p.Gly312Val
|
0
|
0.00
|
0
|
0.00
|
2
|
1.72
|
0.580
|
Abbreviation: PKU, phenylketonuria; cPKU, classic phenylketonuria; mPKU, mild phenylketonuria; MHP, mild hyperphenylalaninemia; RF, relative frequency.
#, significant difference among the three PAHD phenotypes.
Table 4. Genotype-phenotype correlations in PAHD patients
Genotype
|
Protein effect or trivial name
|
Residual activity
(%)*
|
Mean activity
(%)**
|
Predicted phenotype based on activity***
|
GPV
|
Predicted Phenotype
based on GPV
|
Observed phenotype
|
RF(%)
|
cPKU
|
mPKU
|
MHP
|
c.1068C>A/c.721C>T
|
p.Tyr356Ter/p.Arg241Cys
|
null/57
|
28.5
|
cPKU-mPKU
|
5.5
|
mPKU
|
|
1
|
|
1.11
|
c.1138del/c.158G>A
|
p.Thr380ArgfsTer20/p.Arg53His
|
null/79
|
39.5
|
mPKU
|
9.5
|
MHP
|
|
|
1
|
1.11
|
c.1162G>A/c.158G>A
|
p.Val388Met/p.Arg53His
|
28/79
|
53.5
|
MHP
|
9.5
|
MHP
|
|
|
1
|
1.11
|
c.1162G>A/c.721C>T
|
p.Val388Met/p.Arg241Cys
|
28/57
|
42.5
|
mPKU
|
5.5
|
mPKU
|
|
1
|
1
|
2.22
|
c.1174T>A/c.331C>T
|
p.Phe392Ile/p.Arg111Ter
|
98/null
|
49
|
MHP
|
8
|
MHP
|
|
|
1
|
1.11
|
c.1174T>A/c.721C>T
|
p.Phe392Ile/p.Arg241Cys
|
98/57
|
77.5
|
MHP
|
8
|
MHP
|
|
|
2
|
2.22
|
c.1174T>A/c.842C>T
|
p.Phe392Ile/p.Pro281Leu
|
98/2
|
50
|
MHP
|
8
|
MHP
|
|
|
1
|
1.11
|
c.1174T>A/c.422-1G>A
|
p.Phe392Ile/p.IVS4-1G>A
|
98/null
|
49
|
MHP
|
8.0
|
MHP
|
|
|
1
|
1.11
|
c.1197A>T/c.158G>A
|
p.Val399=/p.Arg53His
|
null/79
|
39.5
|
mPKU
|
9.5
|
MHP
|
|
|
2
|
2.22
|
c.1197A>T/c.782G>A
|
p.Val399=/p.Arg261Gln
|
null/44
|
22
|
cPKU
|
1.6
|
cPKU
|
|
|
1
|
1.11
|
c.1197A>T/c.331C>T
|
p.Val399=/p.Arg111Ter
|
null/null
|
0
|
cPKU
|
0.7
|
cPKU
|
1
|
1
|
|
2.22
|
c.1197A>T/c.728G>A
|
p.Val399=/p.Arg243Gln
|
null/14
|
14
|
cPKU
|
0.7
|
cPKU
|
|
1
|
|
1.11
|
c.1197A>T/c.1217T>G
|
p.Val399=/p.Ile406Arg
|
null/n.d.
|
n.d.
|
n.d.
|
n.d.
|
n.d.
|
1
|
|
|
1.11
|
c.1197A>T/c.611A>G
|
p.Val399=/p.Ex6-96A>G
|
null/null
|
0
|
cPKU
|
0.7
|
cPKU
|
1
|
|
|
1.11
|
c.1199G>A/c.842C>T
|
p.Arg400Lys/p.Pro281Leu
|
n.d./0
|
n.d.
|
n.d.
|
0
|
cPKU
|
|
1
|
|
1.11
|
c.1199G>A/c.721C>T
|
p.Arg400Lys/p.Arg241Cys
|
n.d./57
|
n.d.
|
n.d.
|
5.5
|
mPKU
|
|
1
|
|
1.11
|
c.1223G>A/c.1174T>A
|
p.Arg408Gln/p.Phe392Ile
|
41/98
|
69.5
|
MHP
|
8.0
|
MHP
|
|
|
2
|
2.22
|
c.1223G>A/c.721C>T
|
p.Arg408Gln/p.Arg241Cys
|
41/57
|
49
|
MHP
|
5.5
|
mPKU
|
|
|
2
|
2.22
|
c.1223G>A/c.722G>A
|
p.Arg408Gln/p.Arg241His
|
41/23
|
32
|
mPKU
|
5.2
|
mPKU
|
|
1
|
|
1.11
|
c.1223G>A/c.1223G>A
|
p.Arg408Gln/p.Arg408Gln
|
41/41
|
41
|
mPKU
|
5.2
|
mPKU
|
|
1
|
|
1.11
|
c.1223G>A/c.331C>T
|
p.Arg408Gln/p.Arg111Ter
|
41/null
|
20.5
|
cPKU
|
5.2
|
mPKU
|
|
1
|
|
1.11
|
c.1238G>C/c.721C>T
|
p.Arg413Pro/p.Arg241Cys
|
11/57
|
34
|
mPKU
|
5.2
|
mPKU
|
1
|
1
|
|
2.22
|
c.1238G>C/c.331C>T
|
p.Arg413Pro/p.Arg111Ter
|
11/null
|
5.5
|
cPKU
|
0
|
cPKU
|
1
|
|
|
1.11
|
c.1256A>G/c.971T>A
|
p.Gln419Arg/p.Ile324Asn
|
72/n.d.
|
n.d.
|
n.d.
|
9.7
|
MHP
|
|
|
1
|
1.11
|
c.103A>G/.158G>A
|
p.Ile35Val/p.Arg53His
|
n.d./79
|
n.d.
|
n.d.
|
n.d.
|
n.d.
|
|
|
1
|
1.11
|
c.158G>A/c.442-1G>A
|
p.Arg53His/p.IVS4-1G>A
|
79/null
|
39.5
|
mPKU
|
9.5
|
MHP
|
|
|
4
|
4.44
|
c.158G>A/c.1073T>G
|
p.Arg53His/p.Leu358Ter
|
79/null
|
39.5
|
mPKU
|
9.5
|
MHP
|
|
|
1
|
1.11
|
c.158G>A/c.1217T>G
|
p.Arg53His/p.Ile406Arg
|
79/n.d.
|
n.d.
|
n.d.
|
9.5
|
MHP
|
|
|
1
|
1.11
|
c.158G>A/c.331C>T
|
p.Arg53His/p.Arg111Ter
|
79/null
|
39.5
|
mPKU
|
9.5
|
MHP
|
|
|
2
|
2.22
|
c.158G>A/c.60G>C
|
p.Arg53His/p.Gln20His
|
79/n.d.
|
n.d.
|
n.d.
|
9.5
|
MHP
|
|
|
1
|
1.11
|
c.158G>A/c.722del
|
p.Arg53His/p.Arg241ProfsTer100
|
79/null
|
39.5
|
mPKU
|
9.5
|
MHP
|
|
|
2
|
2.22
|
c.158G>A/c.728G>A
|
p.Arg53His/p.Arg243Gln
|
79/14
|
46.5
|
MHP
|
9.5
|
MHP
|
|
|
6
|
6.66
|
c.168+1G>C/c.1174T>A
|
p.IVS2+1G>C/p.Phe392Ile
|
null/98
|
49
|
MHP
|
8.0
|
MHP
|
|
|
1
|
1.11
|
c.473G>A/c.464G>A
|
p.Arg158Gln/p.Arg155His
|
10/44
|
27
|
cPKU
|
10
|
MHP
|
|
|
1
|
1.11
|
c.526C>T/c.1197A>T
|
p.Arg176Ter/p.Val399=
|
null/null
|
0
|
cPKU
|
0.7
|
cPKU
|
2
|
|
|
2.22
|
c.611A>G/c.158G>A
|
p.Ex6-96A>G/p.Arg53His
|
null/79
|
39.5
|
mPKU
|
9.5
|
MHP
|
|
|
2
|
2.22
|
c.611A>G/c.331C>T
|
p.Ex6-96A>G/p.Arg111Ter
|
null/null
|
0
|
cPKU
|
0
|
cPKU
|
1
|
|
|
1.11
|
c.611A>G/c.721C>T
|
p.Ex6-96A>G/p.Arg241Cys
|
null/57
|
28.5
|
cPKU-mPKU
|
5.5
|
mPKU
|
|
2
|
|
2.22
|
c.611A>G/c.1043T>C
|
p.Ex6-96A>G/p.Leu348Pro
|
null/25
|
12.5
|
cPKU
|
0
|
cPKU
|
1
|
|
|
1.11
|
c.721C>T/c.158G>A
|
p.Arg241Cys/p.Arg53His
|
57/79
|
68
|
MHP
|
9.5
|
MHP
|
|
|
3
|
3.33
|
c.721C>T/c.353T>G
|
p.R241C/p.Val118Gly
|
57/n.d.
|
n.d.
|
n.d.
|
n.d.
|
n.d.
|
|
|
1
|
1.11
|
c.721C>T/c.721C>T
|
p.Arg241Cys/p.Arg241Cys
|
57/57
|
57
|
MHP
|
5.5
|
mPKU
|
|
|
2
|
2.22
|
c.721C>T/c.728G>A
|
p.Arg241Cys/p.Arg243Gln
|
57/14
|
35.5
|
mPKU
|
5.5
|
mPKU
|
|
3
|
|
3.33
|
c.728G>A/c.1174T>A
|
p.Arg243Gln/p.Phe392Ile
|
14/98
|
56
|
MHP
|
8.0
|
MHP
|
|
|
2
|
2.22
|
c.728G>A/c.1256A>G
|
p.Arg243Gln/p.Gln419Arg
|
14/71
|
42.5
|
mPKU
|
9.7
|
MHP
|
|
|
1
|
1.11
|
c.728G>A/c.910C>A
|
p.Arg243Gln/p.Gln304Lys
|
14/n.d.
|
n.d.
|
n.d.
|
n.d.
|
n.d.
|
1
|
|
|
1.11
|
c.740G>T/c.331C>T
|
p.Gly247Val/p.Arg111Ter
|
4/null
|
2
|
cPKU
|
0
|
cPKU
|
1
|
|
|
1.11
|
c.755G>A/c.722del
|
p.Arg252Gln/p.Arg241ProfsTer100
|
15/null
|
7.5
|
cPKU
|
0
|
cPKU
|
1
|
|
|
1.11
|
c.782G>A/c.158G>A
|
p.Arg261Gln/p.Arg53His
|
44/79
|
61.5
|
MHP
|
9.5
|
MHP
|
|
|
1
|
1.11
|
c.827T>A/c.158G>A
|
p.Met276Lys/p.Arg53His
|
35/79
|
57
|
MHP
|
9.5
|
MHP
|
|
|
1
|
1.11
|
c.842+2T>A/c.1223G>A
|
p.IVS7+2T>A/p.Arg408Gln
|
null/41
|
20.5
|
cPKU
|
5.2
|
mPKU
|
|
1
|
|
1.11
|
c.856G>A/c.158G>A
|
p.Glu286Lys/p.Arg53His
|
1/79
|
40
|
mPKU
|
9.5
|
MHP
|
|
|
1
|
1.11
|
c.856G>A/c.721C>T
|
p.Glu286Lys/p.Arg241Cys
|
1/57
|
29
|
cPKU-mPKU
|
5.2
|
mPKU
|
|
2
|
|
2.22
|
c.898G>T/c.464G>A
|
p.Ala300Ser/p.Arg155His
|
65/44
|
54.5
|
MHP
|
9.7
|
MHP
|
|
|
1
|
1.11
|
c.913-7A>G/c.721C>T
|
p.IVS8-7A>G/p.Arg241Cys
|
null/57
|
28.5
|
cPKU-mPKU
|
5.5
|
mPKU
|
|
2
|
|
2.22
|
c.913-7A>G/c.730C>T
|
p.IVS8-7A>G/p.Pro244Ser
|
null/n.d./null
|
n.d.
|
n.d.
|
n.d.
|
n.d.
|
|
1
|
|
1.11
|
c.1065+39G>T/c.1223G>A
|
p.IVS10+39G>T/p.Arg408Gln
|
null/41
|
20.5
|
cPKU
|
n.d.
|
n.d.
|
1
|
|
|
1.11
|
c.913-7A>G/c.1174T>A
|
p.IVS8-7A>G/p.Phe392Ile
|
null/98
|
49
|
MHP
|
8.0
|
MHP
|
|
|
1
|
1.11
|
c.913-7A>G/c.611A>G
|
p.IVS8-7A>G/p.Ex6-96A>G
|
null/null
|
0
|
cPKU
|
0
|
cPKU
|
|
|
1
|
1.11
|
c.935G>T/c.158G>A
|
p.Gly312Val/p.Arg53His
|
7/79
|
43
|
mPKU
|
9.5
|
MHP
|
|
|
1
|
1.11
|
c.935G>T/c.838G>A
|
p.Gly312Val/p.Glu280Lys
|
7/11
|
9
|
cPKU
|
0
|
cPKU
|
|
|
1
|
1.11
|
c.964G>A/c.755G>A
|
p.Ala322Thr/p.Arg252Gln
|
n.d./15
|
n.d.
|
n.d.
|
0
|
cPKU
|
|
|
1
|
1.11
|
|
|
|
|
|
|
|
|
|
|
|
|
Abbreviation: n.d.: not determined. PKU, phenylketonuria; cPKU, classic phenylketonuria; mPKU, mild phenylketonuria; MHP, mild hyperphenylalaninemia; RF, relative frequency; GPV, genotypic phenotype value.
*: PAH in vitro residual activity for each mutant protein was assessed from data compiled in the BIOPKUdb (http://www.biopku.org/home/biopku.asp). **: Mean activity is defined as the average sum of activities of both two alleles, and expressed as the percentage of the wild-type enzyme. ***: The expected phenotypes were predicted by the mean of the two allelic activities. The activity cut-off was the following: cPKU, 21.1% ± 7.0%; mPKU, 40.2% ± 7.6%; MHP, 52.1% ± 8.5%. cPKU-mPKU means the activity was between cPKU and mPKU.
Table 5. Pathological analysis of the 5 novel variants of the PAH gene detected in this study
NO.
|
Mutation type
|
cDNA Aberration
|
Protein effect or
trivial name
|
PolyPhen-2
|
Provean
|
Mutation Taster
|
1
|
Missense
|
c.103A>G
|
(p.Ile35Val)
|
Benign
|
Neutral
|
polymorphism
|
2
|
c.1217T>G
|
(p.Ile406Arg)
|
Probably damaging
|
Deleterious
|
Disease causing
|
3
|
c.353T>G
|
(p.Val118Gly)
|
Probably damaging
|
Deleterious
|
Disease causing
|
4
|
Nonsense
|
c.1073T>G
|
(p.Leu358Ter)
|
|
Deleterious
|
Disease causing
|
5
|
Splice
|
c.168+1G>C
|
(p.IVS2+1G>C)
|
|
|
Disease causing
|