| Amino Acid Substitution |
Mutation Name |
Disease |
Genetics |
Frequency |
Reference |
| R3P |
8 g→c
(exon 2) |
PEO |
ar |
(Van Goethem et al., 2001) reported 0 out of 229 control
Individuals (<0.4%) |
(Van Goethem et al., 2001) |
| G11D |
32 g→a
(exon 2) |
Ataxia Neuropathy
Alpers
Alpers
|
Found in cis with R627Q and in trans with R852C, and also found as a Heterozygous mutation with a failure to thrive
Found in cis w/R852C and in trans w/W748S. In a second pt. found in cis w/R852C and in trans w/A467T.
Found in cis w/R852C and in trans w/ A467T. In a 2nd pt., found in cis w/ R852C and in trans w/W748S and E1143G.
|
|
(Wong et al., 2008)
(Ashley et al., 2008)
(Stewart et al., 2008) |
| P18S |
52 t→g
(exon 2) |
Neutral polymorphism |
|
0.6% of 450 individuals |
(GeneSNPs, 2004) |
| ±Glu at aa 43-55 |
±(CAG)n at nucleotides 126 to 162
(exon 2) |
Male infertility, testicular cancer
Idiopathic sporadic Parkinson |
Deletion / Addition of trinucleotide unit. Although initial reports implicated deletion or addition of a trinucleotide unit in male infertility several recent reports refute this notion.
Increase frequency of non-10/11 (CAG) variant in Parkinson disease (PD) |
Rovio et al., 2001 reported 88% of both Finnish and ethnically mixed populations carry the predominant allel of 10 CAG repeats.
Nowak et al., 2005 reported 11% healthy Polish men (n=55) were heterozygous, and 26% of testicular cancer patients (n=49) were heterozygous for the CAG repeats â 10. With no clinical differences in tumor pathology.
Luoma, 2007: found in 10% PD patients compared with 3.5-4.3% spouse/population controls. |
(Rovio et al., 2001)
(Jensen et al., 2004; Ropp and Copeland, 1996)
(Aknin-Seifer et al., 2005; Brusco et al., 2006; Harris et al., 2006; Krausz et al., 2004; Malyarchuk et al., 2005; Nowak et al., 2005)
(Luoma et al., 2007) |
| Q43R |
128 a→g |
Idiopathic sporadic Parkinson |
|
|
(Luoma et al., 2007) |
| Q49E |
145 c→g |
Neutral polymorphism |
|
<1 % in control populations |
(Luoma et al., 2007) |
| S64L |
191 c→t |
Neutral polymorphism |
Found in cis with R232H in ar Charcot-Marie-Tooth
|
30.6% of control population (90/294 control alleles) |
(Harrower et al, 2008) |
| Q68X |
202 c→t
(exon 2)
|
Alpers |
Found in trans w/ A467T
|
|
(Wong et al., 2008)
|
| L83P |
248 t→c
(exon 2) |
Alpers |
Compound heterozygous with G888S in 10 yr old |
|
(Bao et al., 2007)
(Wong et al., 2008) |
| G888S |
2662 g→a (exon 17) |
Alpers |
Compound heterozygous with L83P in 10 yr old |
|
(Bao et al., 2007)
(Wong et al., 2008) |
| H110Y |
328 c→t (exon 2)
|
|
Heterozygous, hypotonia, failure to thrive, short stature, respiratory failure
|
|
(Wong et al., 2008)
|
| A143V |
427 g→c
(exon 2) |
Alpers |
|
Sarzi et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA |
(Sarzi et al. 2007) |
| R193Q |
578 g→a
(exon 2) |
Neutral polymorphism |
|
0.6% of 450 individuals |
(GeneSNPs, 2004) |
| C224Y |
671 g→a
(exon 3) |
Alpers |
|
Sarzi et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA |
(Sarzi et al. 2007) |
| R227W |
679 c→t
(exon 3) |
PEO
Alpers, Severe childhood multi-system disorder |
Sporadic / unknown. Found as compund with T251I.
Also found as compound w/ S1176L
In Alpers found as compound with A467T. In severe childhood multi-system disorder found as compound with D1184N |
Augostino et al. reported 1 out of 27 (3.7%)patients w/
sporadic PEO.
De Vries et al., 2006 identified 3 (14.28%) children out of 21 that were known to have a mitochondrial disorder |
(Agostino et al., 2003)
(de Vries et al., 2006; Lamantea and Zeviani, 2004) |
| R227P |
680 g→c
(exon 3) |
Severe childhood multi-system disorder |
Compound heterozygous with A467T |
De Vries et al. , 2006 identified 1 (4.76%) child out of 21 that were known to have a mitochondrial disorder |
(de Vries et al., 2006) |
| R232G |
694 c→g
(exon 3) |
Infantile hepatocerebral
Alpers |
Found as compound with T251I and P587L
Found in trans w/ [T251I and P587L] |
Ferrari et al., 2005 reported 1 in 9 (11.11%) children with a combination of progressive neurological and hepatic failure, with an allelic frequency of <0.14% (0 out of 350) in the control group. |
(Ferrari et al., 2005)
(Ashley et al., 2008) |
| R232H |
695 g→a
(exon 3) |
Alpers
Charcot-Marie Tooth disease, (CMT) (profound cerebellar ataxia) |
Found as compound in trans with W748S - E1143G
Found in cis with the S64L SNP and in trans with G737R |
Not found in 200 control alleles
Not detected in 282 control alleles |
(Kollberg et al., 2006)
(Harrower et al, 2008)
|
| W235stop |
705 g→a
(exon 3) |
Severe childhood multi-system disorder |
Found as compound heterozygote with A467T |
|
(de Vries et al., 2006) |
| P241L |
722 c→t |
Neutral polymorphism |
|
<1 % in control populations |
(Luoma et al., 2007) |
| L244P |
731 t→c
(exon 3) |
Alpers |
Found as compound with W748S |
Ferrari et al., 2005 reported 1 in 9 (11.11%) children with a combination of progressive neurological and hepatic failure, with an allelic frequency of <0.14% (0 out of 350) in the control group |
(Ferrari et al., 2005) |
| T251I |
752 c→t
(exon 3) |
PEO
Infantile hepatocerebral syndrome
Alpers
PEO
|
ar in PEO, Found as compound with R309L, or 2354G insertion, or G848S in PEO.
Frequently found in cis with P587L and compound in trans with N864S, R807P, H932Y, V1106I, or R709stop. Found as compound with R227W
In Infantile hepatocerebral found in cis with P587L and compound with R232G
Found in trans w/ G848S and in cis w/ P587L. Also found in cis w/P587L and in trans w/R853Q in myocerebrohepato-pathy patient. Also found as a hetero. Mutation with ataxia, ptosis, and neuropathy. Found in trans w/ R232G and cis w/ P587L.
Found in cis w/ P587L, with both mutations on each allel. A 2nd pt found to have P587L in trans and A467T in cis.
|
Ferrari et al., 2005 reported 1 in 9 (11.11%) children with a combination of progressive neurological and hepatic failure, with a heterozygous frequency of 1% of Italian controls.
Horvath et al., 2006 reported a 1.11% (5 out of 450) allelic frequency in Italian controls and always with P587L
Van Goethem, 2003: Not found in 280 control chromosomes |
(Lamantea et al., 2002)
(Agostino et al., 2003; Di Fonzo et al., 2003; Lamantea and Zeviani, 2004; Van Goethem et al., 2003c)
(Ferrari et al., 2005; Gonzalez - Vioque et al., 2006)
(Horvath et al., 2006; Kollberg et al., 2005)
(Wong et al., 2008)
(Ashley et al., 2008)
(Stewart et al., 2008)
|
| G268A |
803 g→c
(exon 3) |
PEO |
Sporadic / unknown
Found as compound in trans with A467T |
Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians
Gonzalez - Vioque 2006: Not detected in 100 control subjects |
(Del Bo et al., 2003)
(Baruffini et al., 2006; Di Fonzo et al., 2003; Gonzalez - Vioque et al., 2006) |
| H277C |
829,830 ca→tg
(exon 3) |
Alpers |
Found in trans w/T851A |
|
(Ashley et al., 2008) |
| L304R |
911 t→g
(exon 4) |
PEO
Ataxia - neuropathy
Alpers |
ar
Compound in trans with A467T
Found as homozygous or compound in trans with W748S - E1143G in SCAE, ataxi-neuropathy
Found homozygous in one pt. |
(Van Goethem et al., 2001) reported 0 out of 229 control
Individuals (<0.4%) |
(Naimi et al., 2006; Stuart et al., 2006; Van Goethem et al., 2001)
(Ashley et al., 2008) |
| S305R |
915 c→g
(exon 4) |
Alpers? |
heterozygous |
|
(Wong et al., 2008) |
| Q308H |
924 g→c
(exon 4) |
PEO |
ar Compound with T914P-F1164I |
Horvath et al., 2006 reported 0 out of 200 (0%) allelic frequency in Italian controls |
(Horvath et al., 2006) |
| R309L |
926 g→t
(exon 4) |
PEO |
ar
Compound with T251I |
Not found in 100 DNA samples |
(Lamantea et al., 2002) |
| R309H |
926 g→a
(exon 4) |
Alpers |
Compound in trans with R627Q |
Horvath et al., 2006 reported 10% (1 out of 10) patients with encephalopathy and liver failure |
(Horvath et al., 2006) |
| W312R |
934 t→c
(exon 4) |
PEO +/-
dysphagia/myopathy |
Sporadic or ar
Found in trans with R574W. |
Not found in 250 control individuals |
(Agostino et al., 2003)
(Horvath et al., 2006) |
| P324S |
970 t→g
(exon 4) |
Neutral polymorphism |
|
0.6% of 450 individuals |
(GeneSNPs, 2004) |
| T326fsX387 |
975-976 ins c
(exon 4) |
Alpers |
Found in trans with A467T |
|
(Naimi et al., 2006) |
| W347_L356 del |
1039-1068 del
(exon 5) |
Alpers |
10 amino acid del found in trans w/A467T |
|
(Ashley et al., 2008) |
| R374X |
1120 c→t (STOP)
(exon 5) |
Alpers |
Found in trans w/A467T. |
|
(Ashley et al., 2008) |
| G380D |
1139 g→a
(exon 5) |
PEO |
Sporadic mutation found in trans with A467T |
Not found in 300 healthy French control chromosomes |
(Naimi et al., 2006) |
| L392V |
1174 c→g |
Neutral polymorphism |
Heterozygous with muscle weakness & optic atrophy
|
<1 % in control populations |
(Luoma et al., 2007)
(Wong et al., 2008) |
| R417T |
1250 g→c
(exon 6&7 junction) |
Alpers |
Found in trans w/A467T |
|
(Ashley et al., 2008) |
| C418R |
1252 t→c |
Alpers? |
Found in trans w/A467T. |
|
(Ashley et al., 2008) |
| L424GfsX28 (CT)deletion - 452stop |
1270-1271 del ct
(exon 7) |
PEO
Alpers |
Sporadic / unknown Compound with G431V
Found in trans with A467T |
Not found in a control series of 250 individuals |
(Agostino et al., 2003)
(Wong et al., 2008) |
| L428P |
1283 t→c
(exon 7) |
Alpers |
|
Sarzi et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA were found with the mutation L428P. 19% (9 out of 50) had various mutations in POLG. |
(Sarzi et al. 2007) |
| M430L |
1279 a→t (exon 7) |
PEO with Parkinsonism |
ar, Compound (in trans) heterozygous with W918R |
Absent in 200 control alleles |
(Invernizzi et al., 2008) |
| G431V |
1292 g→t
(exon 7) |
PEO |
Sporadic / unknown
Compound with L424 CT deletion |
Not found in a control series of 250 individuals |
(Agostino et al., 2003) |
| S433C |
1298 c→g
(exon 7) |
PEO- ataxia, peripheral neuropathy |
Sporadic, Found in trans with E1143G |
Hudson, 2006: Not detected in 200 controls |
(Hudson et al., 2006a)
(Horvath et al., 2006) |
| T452stop |
1356 t→g
(exon 7) |
PEO |
Sporadic |
Not detected in 200 controls. |
(Hudson et al., 2006a) |
| L463F |
1389 g→t
(exon 7) |
PEO |
ar, Found as compound in trans with S511N |
None found in 192 ethnically matched
control chromosomes nor in 108 patients with PEO and
140 cases of sporadic PD |
(Hudson et al., 2006b) |
| A467T |
1399 g→a
(exon 7) |
PEO, SANDO, MERRF, Ataia-Neuropathy, ataxia - myopathy, Alpers, severe childhood multi-system disorder
Alpers w/ valporate induced hepatic failure
Alpers, Ataxia
Neuropathy, and arPEO+
Alpers
Alpers, PEO
|
Most commonly found disease mutation in POLG and appears to be recessive, this mutation disrupts subunit interaction and lowers DNA binding and catalytic efficiency of polymerase.
ar in PEO, Found as compound with L304R or R3P, or G268A in PEO. Found as compound with R627W in SANDO. Found as compound with S1104C.
Found in compound het with E873stop or as compound het with W1020stop in Alpers. Found as a homozygous mutation in Alpers and ataxia.
Found as compound in trans with R627Q, Q1236H, and W748S - E1143G in ataxia - neuropathy.
Found as compound in trans in Alpers with R574W, G848S, A957P, E1143G + W748S, or 3482+2T to C. Found as homozygous mutation in PEO patient with ptosis and sensorimotor neuropathy. In severe childhood multi-system disorder this mutation found as homozygous or compound with R227W, G848S, A957P, W235stop, or R227P
Found in cis w/T885s and in trans w/Q879H and E1143G.
Found in trans w/ L886P, Q68X, Q715X, T849H, T914P, L83P, G888S, R1138C, c.2480+1, c. 2157+5, G737R, and L424G
Found in trans w/ [R852C and G11D], and, found in trans w/ T914P in 2 additional pts.
In trans w/E873X.
In trans w/
W347_L356 del.
In trans w/G848S.
In trans w/L966R.
In trans w/R374X.
In trans w/ R417T.
In trans w/C418R.
One pt, found as a homozygous mutation.
Found in trans w/L605R, and in a 2nd pt in trans w/ W748S. Also, found as a homozygous mutation.
Found in trans w/ T251I and P587L. Also found in trans w/ G11D and R852C. Also found in trans w/G848S.
|
Van Goethem, 2003: 0.6% in Belgium population,
0.69% in British population,
and 1% in Norway population |
(Van Goethem et al., 2001)
(Agostino et al., 2003; Chan et al., 2005a; Chan et al., 2005b; Di Fonzo et al., 2003; Ferrari et al., 2005; Naviaux and Nguyen, 2004; Naviaux and Nguyen, 2005; Van Goethem et al., 2004; Van Goethem et al., 2003a; Van Goethem et al., 2003b)
(Gonzalez - Vioque et al., 2006; Luoma et al., 2005; Nguyen et al., 2005; Stuart et al., 2006; Winterthun et al., 2005)
(Horvath et al., 2006)
( Kollberg et al., 2006; Naimi et al., 2006; Tzoulis et al., 2006)
(McFarland et al., 2008)
(Wong et al., 2008)
(Ashley et al, 2008)
(Stewart et al., 2008)
|
| N468D |
1402 a→g
(exon 7) |
PEO |
ar |
Luoma, 2004: None noted in screening of 1640 healthy Finnish control chromosomes. |
(Luoma et al., 2004; Wanrooij et al., 2004) |
| Q497H |
1491 g→c
(exon 8) |
ataxia - neuropathy
Alpers, Ataxia Neuropathy |
Found allelic (cis) with W748S + E1143G
In cis with G848S and in trans with W748S-E1143G. also found in trans w/ A467T. |
1 in 97 found in healthy controls and 1 in 99 found mtDNA disease patients |
(Winterthun et al., 2005)
(Wong et al., 2008) |
| S511N |
1532 g→a
(exon 8) |
PEO |
ad |
None found in 192 ethnically matched
control chromosomes nor in 108 patients with PEO and
140 cases of sporadic PD |
(Hudson et al., 2006b) |
| G517V |
1550 g→t
(exon 7) |
ataxia - neuropathy
Myopathy and micro-cephaly
adPEO |
ad
Found in trans w/ D1196N and R1128H
Heterozygous, short-stature, Leigh-like disease, neuropathy, stroke, dystonia, chorea, diabetes, myoclonus, Sideroblastic anemia, splenmegaly, Pearson Syndrome to KSS |
Horvath et al., 2006 reported 1 out of 672 allelic frequency in German controls |
(Horvath et al., 2006)
(Wong et al., 2008)
(Wong et al., 2008) |
| R546C |
1636 c→t
(exon 9) |
Neutral polymorphism |
1% |
1.1% of 450 individuals |
(GeneSNPs, 2004) |
| K561M |
1882 a→t
(exon 9) |
Dysmorphy, hypotonia, coloboma, heart failure, and liver insufficiency |
Compound heterozygosity in cis with W748S |
Sarzi et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA were found with the mutation K561M in cis with W748S. |
(Sarzi et al., 2007) |
| R562Q |
1685 g→a
(exon 9) |
PEO |
sporadic |
Not found in 100 DNA samples from healthy Italians |
(Di Fonzo et al., 2003) |
| H569Q |
1707 c→(a or g)
(exon 9) |
? |
Homozygous |
|
(Ashley et al., 2008) |
| R574W |
1720 c→t
(exon 10) |
PEO + myopathy / dysphagia
Alpers |
ar, Compound in trans with W312R in PEO or in trans with A467T in Alpers |
Horvath et al., 2006 reported 0 out of 200 (0%) allelic frequency in Italian controls
Kollberg, 2006: Not found in 200 control alleles |
(Horvath et al., 2006; Kollberg et al., 2006) |
| R579W |
1735 c→t
(exon 10) |
PEO |
Sporadic / unknown
Compound with A889T |
Not detected in 120 healthy control alleles |
(Filosto et al., 2003) |
| P587L |
1760 c→t
(exon 10) |
PEO
Infantile hepatocerebral
Alpers
Alpers |
ar PEO
Found in cis with T251I and compound with N864S, or R807P, H932Y, G848S, or R709stop.
In Infantile hepatocerebral found in cis with T251I and compound with R232G. Found in trans with R853W in PEO
Found in cis w/ T251I and in trans w/ G848S, also found as a hetero. Mutation with ataxia, ptosis, and neuropathy
Found in trans w/R232G and in cis w/T251I. Also, in cis w/P589L and in trans w/W748S.
Found in cis with T251I with both mutations on each allel. Also, found in cis w/A467T and in trans w/T251I.
|
Filosto, 2003: not detected in 120 healthy control alleles.
Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians
Van Goethem, 2003: Not found in 280 control chromosomes
Ferrari et al., 2005 reported 1 in 9 (11.11%) children with a combiniation of progressive neurological and hepatic failure, with a heterozygous frequency of 1% of Italian controls. |
(Van Goethem et al., 2003c)
(Di Fonzo et al., 2003; Filosto et al., 2003)
(Lamantea and Zeviani, 2004)
(Ferrari et al., 2005; Gonzalez - Vioque et al., 2006; Kollberg et al., 2005)
(Wong et al., 2008)
(Ashley et al., 2008)
(Stewart et al., 2008)
|
| P589L |
1766 c→t
(exon 10) |
Alpers? |
Found in cis w/P587L and in trans w/W748S. |
|
(Ashley et al., 2008) |
| R597W |
1789 c→t (exon 10)
|
PEO with ataxia |
Homozygous |
|
(Stewart et al., 2008) |
| M603L |
1807 a→t
(exon 10) |
PEO with ptosis |
Found as compound in trans with T251I-P587L |
Gonzalez - Vioque 2006: Not detected in 100 control subjects |
(Gonzalez - Vioque et al., 2006) |
| L605R |
1814_1815 tt→gc (exon 10) |
Alpers |
Found in trans w/ A467T. Mitochondria depletion in liver |
|
(Stewart et al., 2008) |
| R617C |
1849 c→t
(exon 10) |
|
Heterozygous with muscle weakness, exercise intolerance, hearing loss, arhythmia |
|
(Wong et al., 2008) |
| R627W |
1879 c→t
(exon 10) |
PEO, SANDO
Alpers |
Ar
Found in trans with A467T
Found in trans w/T914P |
Van Goethem, 2003: absent in 612 Belgian controls. |
(Van Goethem et al., 2003a)
(Horvath et al., 2006)
(Ashley et al., 2008) |
| R627Q |
1880 g→a
(exon 10) |
ataxia - myopathy Alpers PEO - ataxia - nueropathy
MELAS
Ataxia Neurpoathy |
Found in cis with Q1236H and in trans with A467T
Found in compound in trans with R309H or R1096H in Alpers.
Found in cis with Q1236H and in trans with L965stop - E1143G in PEO
Found w/ G848S; heterozygous mutation; w/ mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.
Found in cis w/ G11D and in trans w/ R852C. |
|
(Luoma et al., 2005)
(Horvath et al., 2006)
(Deschauer et al., 2007)
(Wong et al., 2008) |
| P648R |
1943 c→g
(exon 10) |
PEO + myopathy
SANDO |
ar, Found as either homozygous mutation or as compound in trans with R1096C in PEO.
Compound with R807C in SANDO. |
Horvath et al., 2006 reported 0 out of 200 (0%) allelic frequency in Italian controls |
(Gago et al., 2006; Horvath et al., 2006) |
| E662K |
1984 g→a
(exon 11) |
Neutral polymorphism |
|
2.8% of 450 individuals |
(GeneSNPs, 2004) |
| R709stop |
2125 c→t
(exon 12) |
PEO |
Sporadic
Found as compound with T251I-P587L |
Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians |
(Del Bo et al., 2003)
(Di Fonzo et al., 2003) |
| Q715X |
2143 c→t
(exon 12) |
Alpers |
Found in trans w/ A467T |
|
(Wong et al., 2008) |
| c. 2157+5_+6 |
2157 gc→ ag
(exon 12) |
Alpers |
Found in trans with
A467T, most likely a splice site mutation. |
|
(Wong et al., 2008) |
| R722H |
2165 g→a(exon 13) |
Neutral polymorphism |
|
<1 % in control populations |
(Luoma et al., 2007) |
| G737R |
2209 g→c
(exon 13) |
Alpers
Parkinsonism
Charcot-Marie Tooth disease, (CMT) (profound cerebellar ataxia)
arPEO+ and Myocerebrohepatopathy (MCHS) |
Found as compound in trans with A767D Parkinsonism in compound in trans with R853W
Found in trans with the S64L-G737R in CMT
Found in trans w/ A467T. In trans w/
E1143G-R943C in MCHS.
Found as a heterozygous mutation. |
Horvath et al., 2006 reported 2 out of 666 allelic frequency in German controls
Found in 2/666 (0.3%) of control alleles |
(Horvath et al., 2006)
(Davidzon et al., 2006)
(Harrower et al, 2008)
(Wong et al., 2008)
(Wong et al., 2008) |
| G746S |
2236 g→a(exon 13) |
Ataxia, PEO |
Found in cis w/ E1143G, and in trans G848S |
1in 454 alleles |
(Stewart et al., 2008) |
| W748S |
2243 g→c
(exon 13) |
ataxia - neuropathy, Alpers
Alpers, Ataxia Neuropathy, and arPEO+
Alpers
Alpers
PEO and Alpers
|
Usually found in cis with E1143G. Compound w/ 3630insC, also found as compound with L244P, G848S, and Y1210fs1216stop in Alpers. Found in compound with Q497H, L304R, or A467T in SCAE.
Homozygous W748S +E1143G in ataxia - neuropathy and multiple respiratory chain deficiency.
Found in trans w/ G848S, and in cis w/ Q479H-E1143G.
Also found in trans w/ A467T. arPEO+ as a compound w/ E1143G
Homozygous, juvenile onset
Found in trans w/ [R852C and G11D], and found in 2 additional pts
in trans w/T914P.
Found homozygous in one pt. Found in trans w/ G848S.
Found in trans w/[P587L and P589L].
Found in trans w/ A467T. In a 2nd pt., found in cis w/ E1143G and in trans w/ G11D and R852C.
|
Sarzi, et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA were found with the mutation W748S with E1143G.
1% of Norwegians and
0.8% of Finns
Winterthun, 2005: 1 in 97 found in healthy controls and 1 in 99 found mtDNA disease patients |
(Van Goethem et al., 2004)
(Davidzon et al., 2005; Ferrari et al., 2005)
(Hakonen et al., 2005; Nguyen et al., 2005; Winterthun et al., 2005)
(Horvath et al., 2006; Naimi et al., 2006; Tzoulis et al., 2006; Chan et al., 2006)
(Sarzi, et al. 2007)
(Wong et al., 2008)
(Uusimaa et al., 2008)
(Ashley et al., 2008)
(Stewart et al., 2008)
|
| F749S |
2246 t→c
(exon 13) |
Alpers |
Found as compound with A467T |
Not found in 300 control chromosomes |
(Nguyen et al., 2006) |
| G763R |
2287 g→c
(exon 14) |
PEO, SANDO |
ar, Found as a homozygous mutation in PEO-SANDO |
Not found in 500 ethnically-matched control chromosomes |
(Santoro et al., 2006) |
| A767D |
2300 c→a
(exon 14) |
Alpers |
Found as compound in trans with G737R |
Not found in 678 alleles of German descent |
(Horvath et al., 2006) |
| 2354Gins at G785 |
2354 ins g
STOP @ CODON 806
(exon 14) |
PEO |
ar Compound with T251I |
Absent in 100 control DNA samples |
(Lamantea et al., 2002) |
| R807P |
2420 g→c
(exon 14) |
PEO |
Sporadic Compound with T251I-P587L |
Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians |
(Del Bo et al., 2003)
(Di Fonzo et al., 2003) |
| R807C |
2419 c→t
(exon 14) |
SANDO |
Compound with P648R |
Not found in 200 ethnically matched control chromosomes |
(Gago et al., 2006) |
| c. 2480+1 |
2480+1 g→a
splice
(exon 15) |
Alpers |
Found in trans w/ W748S-E1143G |
|
(Wong et al., 2008) |
| IVS15 - 9 - c.2485del 12bp |
2485 del 12bp
(exon 16) |
Alpers |
Splice site mutation
3'exon15/intron junction, Found in trans with A467T |
1 found in 666 German controls alleles |
(Horvath et al., 2006) |
| Y831C |
2492 a→g
(exon 16) |
Most likely a neutral polymorphism, but found in PEO and parkinsonism. |
Ad in PEO and Parkinsonism. Found in high percentage in healthy controls in three studies.
Heterozygous, hypotonia, Autism, neuropathy, ataxia, hearing loss, short stature, muscle weakness, fatigue |
Mancuso 2004: Not seen in 120 control subjects
Stopinska 2006: present in the Polish population at a frequency of 2.25%.
Tiangyou 2006: Found at the same frequency in age-matched controls.
Luoma 2007: Found in <1% of healthy controls |
(Barthelemy et al., 2002; Mancuso et al., 2004b)
(Stopinska et al., 2006; Tiangyou et al., 2006)
(Luoma et al., 2007)
(Wong et al., 2008) |
| G848S |
2542 g→a
(exon 16) |
PEO, Alpers
MELAS
Alpers
Alpers
PEO and Ataxia
|
ar
Compound with T251I and P587L.
Found as compound in Alpers with A467T, W748S and E1143G
Found w/ R627Q; heterozygous mutation; w/ mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.
Found in trans with
A467T, Q497H, W748S, and E1143G. Also found in trans w/ T251I-P587L
Found in trans w/W748S, and in a 2nd pt in trans w/A467T.
In trans w/ G746S and E1143G. Also found in trans w/ A467T.
|
Lamantea, 2002: absent in 100 control DNA samples |
(Lamantea et al., 2002)
(Ferrari et al., 2005)
(Davidzon et al., 2005; Kollberg et al., 2005; Nguyen et al., 2005)
(de Vries et al., 2006; Horvath et al., 2006; Kollberg et al., 2006)
(Deschauer et al., 2007)
(Wong et al., 2008)
(Ashley et al., 2008)
(Stewart et al., 2008)
|
| T849H |
2544 (insertion of c with fs868X)
(exon 16) |
Alpers |
Found in trans with
A467T and in cis with Q1236H |
|
(Wong et al., 2008) |
| T851A |
2551 a→g
(exon 16) |
Alpers
Alpers |
Found in trans w/R1047W.
Found in trans w/H277C. |
Not found in over 100 control alleles |
(Wiltshire et al., 2006)
(Ashley et al., 2008) |
| R852C |
2554 c→t
(exon 16) |
Alpers
Ataxia Neuropathy
Alpers
Alpers
|
Compound with A467T
Found in trans w/
G11D-R627Q
Found in cis w/G11D and in trans w/W748S, and in a 2nd pt found in cis w/G11D and in trans w/A467T.
Found in cis w/G11D and in trans w/ A467T. In a 2nd pt., found in cis w/G11D and in trans w/ W748S and E1143G.
|
Not found in 300 control chromosomes |
(Nguyen et al., 2006)
(Wong et al., 2008)
(Ashley et al., 2008)
(Stewart et al., 2008)
|
| R853W |
2557 c→t
(exon 16) |
PEO with ptosis
Parkinsonism |
Found as compound in trans with P587L Parkinsonism in compound in trans with G737R |
Gonzalez - Vioque 2006: Not detected in 100 control subjects |
(Gonzalez - Vioque et al., 2006)
(Davidzon et al., 2006) |
| R853Q |
2558 g→a
(exon 16) |
Myocerebrohepatopathy |
In trans with T251I-P587L |
|
(Wong et al., 2008) |
| V855A |
2564 t→c
(exon 16) |
|
Heterozygous with muscle weakness. |
|
(Wong et al., 2008) |
| A862T |
2584 g→a
(exon 16) |
Ataxia Neuropathy
PEO+
|
Compound heterozygous with R964C
In trans w/R1047W
|
|
(Wong et al., 2008)
(Stewart et al., 2008)
|
| N864S |
2591 a→g
(exon 16) |
PEO |
Found as compound with T251I-P587L |
Not found in 280 control chromosomes |
(Van Goethem et al., 2003c) |
| E873stop |
2617 g→t
(exon 17) |
Alpers
Alpers |
Found in trans with A467T
Found in trans w/A467T. |
Not found in 40 alleles from non-Alpers mitochondrial disease patients |
(Chan et al., 2005b; Naviaux and Nguyen, 2004; Naviaux and Nguyen, 2005)
(Ashley et al., 2008) |
| Q879H |
2637 g→t
(exon 17) |
Alpers
Alpers w/ valproate-induced hepatic failure |
Found in cis with E1143G and in trans with A467T-T885S
Found in cis w/ A467T and T885S, and in trans w/ E1143 |
Horvath et al., 2006 reported 0 out of 192 (0%) allelic frequency in British controls |
(Horvath et al., 2006)
(McFarland et al., 2008) |
| T885S |
2653 a→t
(exon 17) |
Alpers
Alpers w/ valproate-induced hepatic failure |
Found in cis with A467T and in trans with Q879H-E1143G
Found in cis with A467T, and in trans w/Q879H and E1143G |
Horvath et al., 2006 reported 0 out of 192 (0%) allelic frequency in British controls
|
(Horvath et al., 2006)
(McFarland et al., 2008) |
| L886P |
2657 t→c
(exon 17) |
Alpers |
Found in trans w/ A467T |
|
(Wong et al., 2008) |
| A889T |
2665 g→a
(exon 17) |
PEO |
Sporadic / unknown
Compound with R579W
Compound with E1143G |
Filosto, 2003: not detected in 120 healthy control alleles |
(Filosto et al., 2003)
(Hisama et al., 2005) |
| T914P |
2740 a→c
(exon 18) |
Alpers, Encephalopathy, PEO
Alpers
adPEO
Alpers |
Compound in trans with A467T. In PEO-myopathy found in cis with F1164I and in trans with Q308H
Found in trans w/A467T
Heterozygous, Ptosis, exercise intolerance, fatigue, ragged red fibers
Found in trans w/R1096C, and in a 2nd pt found in trans w/R627W. Also found in trans w/A467T in 2 other pts. Found in 2 additional pts in trans w/W748S. |
Not found in 664 German controls or 200 Italian controls. |
(Nguyen et al., 2006)
(Horvath et al., 2006)
(Naimi et al., 2006)
(Wong et al., 2008)
(Wong et al., 2008)
(Ashley et al., 2008) |
| W918R |
2752 t→c(exon 18) |
PEO with Parkinsonism |
Compound (in trans) heterozygous with M430L |
Absent in 200 control alleles |
(Invernizzi et al., 2008) |
| G923D |
2768 g→a
(exon 18) |
PEO |
ad |
Lamantea, 2002: Not found in a control group of 100 DNA samples from unrelated Italians |
(Lamantea et al., 2002)
(Graziewicz et al., 2004; Stuart et al., 2006) |
| H932Y |
2794 c→t
(exon 18) |
PEO, SANDO |
ar
Found as compound with T251I-P587L
Found as compound with G1051R |
Mancuso 2004: not seen in 120 control subjects.
Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians |
(Di Fonzo et al., 2003)
(Mancuso et al., 2004a) |
| R943C |
2827 c→t
(exon 18) |
Myocerebrohepatopathy |
In cis w/ E1143G and in trans w/G737R |
|
(Wong et al., 2008) |
| R943H |
2828 g→a
(exon 18) |
PEO |
ad |
Lamantea, 2002: Not found in a control group of 100 DNA samples from unrelated Italians |
(Lamantea et al., 2002)
(Graziewicz et al., 2004; Stuart et al., 2006) |
| R953C |
2857 c→t
(exon 18) |
PEO |
ad |
Luoma, 2004: None noted in screening of 1640 healthy Finnish control chromosomes. |
(Luoma et al., 2004) |
| Y955C |
2864 a→g
(exon 18) |
PEO +/-
Parkinsonism
Premature ovarian failure Alzheimer's disease |
ad
Most severe autosomal dominant mutation in POLG, drastically lowers polymerase catalysis, promotes stalling and errors in replication.
Found as a heterozygous mutation w/ hearing loss, failure to thrive, generalized ETC complex defiency |
Lamantea, 2002: Not found in a control group of 100 DNA samples from unrelated Italians
Luoma, 2004: None noted in screening of 1640 healthy Finnish control chromosomes. |
(Van Goethem et al., 2001) (Lamantea et al., 2002) (Graziewicz et al., 2004; Luoma et al., 2004; Pagnamenta et al., 2006; Ponamarev et al., 2002; Stuart et al., 2006) (Baruffini et al., 2006; Kollberg et al., 2005; Lewis et al., 2007; Melberg et al., 2005)
(Wong et al., 2008) |
| A957S |
2869 g→t
(exon 18) |
PEO |
ad PEO |
Lamantea, 2002: Not found in a control group of 100 DNA samples from unrelated Italians
Ferrari, 2005: absent in 200 consecutive control
individuals from Northern continental Europe as well as 350 Italian controls |
(Lamantea et al., 2002)
(Ferrari et al., 2005; Graziewicz et al., 2004; Stuart et al., 2006) |
| A957P |
2869 g→c
(exon 18) |
Alpers |
Found in Alpers as a compound with A467T |
|
(de Vries et al., 2006; Ferrari et al., 2005) |
| F961S |
2882 t → c |
PEO |
ad PEO |
|
(Adachi et al., 2002) |
| R964C |
2890 c → t
(exon 18) |
Mitochondrial toxicity susceptibility to NRTIs
Ataxia Neuropathy |
Found in a HIV1 patient with hyperlactatemia following 1 yr of d4T and 3TC anti-viral treatment
Found in trans w/ A862T, and found as a heterozygous mutation w/ ataxia and hypotonia |
Not found in 26 Thai HIV-1âinfected individuals, or 110 healthy volunteers |
(Yamanaka et al., 2007)
(Wong et al., 2008) |
| L83P |
248 t → c |
Alpers |
Compound heterozygous with G888S in 10 yr old |
|
(Bao et al., 2007) |
| L965stop |
2894 t→g
(exon 18) |
PEO |
ar, found in cis with E1143G and in trans with R627Q-Q1236H |
|
(Horvath et al., 2006) |
| L966R |
2897 t→g
(exon 18) |
Alpers
Alpers |
Compound with A467T
In trans w/A467T. |
Not found in 300 control chromosomes |
(Nguyen et al., 2006)
(Ashley et al., 2008) |
| W1020stop |
3057 g→a
(exon 19) |
Alpers |
Compound with A467T |
|
(Nguyen et al., 2005) |
| R1047Q |
3140 g→a
(exon 20) |
PEO |
Sporadic / unknown |
Not found in 250 control individuals |
(Agostino et al., 2003) |
| R1047W |
3140 g→a
(exon 20) |
Alpers
PEO
|
Compound in trans with T851A
In trans w/ A862T
|
Not found in over 100 control alleles |
(Wiltshire et al., 2006)
(Stewart et al., 2008)
|
| G1051R |
3151 g→c
(exon 20) |
PEO, SANDO |
ar
Found as compound with H932Y |
not seen in 120 control subjects. |
(Mancuso et al., 2004a) |
| G1076V |
3227 g→t
(exon 20) |
PEO |
Sporadic / unknown |
Not detected in 120 healthy control alleles |
(Filosto et al., 2003) |
| I1079L |
3235 a→c
(exon 20) |
adPEO |
Heterozygous
Hearing loss, ptosis |
|
(Wong et al., 2008) |
| S1095R |
3285 c→g
(exon 21) |
adPEO |
Hearing loss, ptosis,
Muscle weakness, optic atrophy |
|
(Wong et al., 2008) |
| R1096C |
3286 c→t
(exon 21) |
PEO
Alpers
Alpers
Alpers |
Sporadic or ar in PEO
Found in trans with P648R in PEO-myopathy.
Found as homozygous mutation with Q1236H in Alpers
Found as compound w/ Q1236H
Found in trans w/T914P, and homozygous in a 2nd pt.
|
Agostino 2003: Not found in 250 individuals |
(Agostino et al., 2003)
(Horvath et al., 2006)
(Wong et al., 2008)
(Ashley et al., 2008)
|
| R1096H |
3287 g→a
(exon 21) |
Alpers |
Found as a compound in trans with R627Q |
|
(Horvath et al., 2006) |
| S1104C |
3311 c→g
(exon 21) |
PEO |
Sporadic / unknown
Found as compound with A467T |
Not found in 250 individuals |
(Agostino et al., 2003) |
| A1105T |
3313 g→a
(exon 21) |
PEO |
Ad |
Luoma, 2004: None noted in screening of 1640 healthy Finnish control chromosomes. |
(Luoma et al., 2004; Wanrooij et al., 2004) |
| V1106I |
3316 g→a
(exon 21) |
PEO |
ar, found in trans with T251I-P587L |
Not found in 500 Italian controls. |
(Horvath et al., 2006) |
| R1128H |
3383g→a
(exon 21) |
Microcephaly |
Heterozygous, found w/ G517V |
|
(Wong et al., 2008) |
| R1138C |
3412 c→t
(exon 21) |
arPEO+ |
Found in trans w/ A467T |
|
(Wong et al., 2008) |
| R1142W |
3424 c→t
(exon 21) |
Neutral polymorphism |
|
0.6% of 450 individuals |
(GeneSNPs, 2004) |
| E1143G |
3428 a→g
(exon 21) |
Neutral polymorphism but may modulate disease mutations
Alpers with valproate-induced hepatic failure
Alpers, Ataxia Neuropathy, and arPEO+
Myocerbrohepato-
Pathy (MCHS)
PEO and Ataxia
|
Has also been found in PEO and ataxia-neuropathy patients. Found in adPEO in cis with A889T
Found in ataxia-neuropathy in cis with W748S and in compound with G848S or A467T.
Found in cis with W748S in Alpers and in compound with L244P, G848S, M1163R or Y1210fs1216stop.
Homozygous W748S +E1143G in ataxia-neuropathy and multiple respiratory chain deficiency.
Found in cis w/ T885S and A467T, and in trans w/ Q879H
Found in trans w/ G848S, and in cis w/Q497H-W748S.
Also found in trans w/ A467T, and in cis w/ Q497H-W748S. Also in cis w/ E1143 and in trans w/ G737R in MCHS.
Found in cis w/ G746S and in trans w/ G848S. In a 2nd pt., found in cis w/W748S and in trans w/ G11D and R852C.
|
SNP at 3.7% of 450 individuals of European descent. Not found in Asian or African populations
Sarzi, et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA were found with the mutation W748S with E1143G. |
(GeneSNPs, 2004)
(Di Fonzo et al., 2003; Van Goethem et al., 2004)
(Hisama et al., 2005)
(Ferrari et al., 2005)
(Davidzon et al., 2005; Nguyen et al., 2005; Winterthun et al., 2005) (Chan et al., 2006; Horvath et al., 2006; Kollberg et al., 2006) (Sarzi, et al. 2007)
(McFarland et al., 2008)
(Wong et al., 2008)
(Stewart et al., 2008)
|
| R1146C |
3436 c→t
(exon 21) |
Neutral polymorphism |
Also found in one patient with muscle atrophy |
0.6% of 450 individuals |
(GeneSNPs, 2004; Gonzalez-Vioque et al., 2006) |
| 3482 +2T to C |
3482 +2tâs
splice at intron 21
(exon 21) |
Alpers |
Exon21/Intron21 splice site mutation at a.a. 1161. Found in trans with A467T |
Horvath 2006, not found in 666 German controls. |
(Ferrari et al., 2005) (Horvath et al., 2006) |
| M1163R |
3488 t→g
(exon 22) |
Alpers |
Found as compound in trans with W748S - E1143G |
Not found in 200 control alleles |
(Kollberg et al., 2006) |
| F1164I |
3490 t→a
(exon 22) |
PEO |
Ar, found in cis with T914P and in trans with Q308H |
Not found in 200 Italian controls |
(Horvath et al., 2006) |
| L1173fs stop |
3518 ins gact,
fs in exon 22
(exon 22) |
Alpers |
Compound with A467T |
Not found in 300 control chromosomes |
(Nguyen et al., 2006) |
| S1176L |
3527 c→t
(exon 22) |
PEO |
ar
Found as compound w/ R227W |
Lamantea, 2002: Not found in a control group of 100 DNA samples from unrelated Italians |
(Lamantea et al., 2002)
(Lamantea and Zeviani, 2004) |
| D1184N |
3550 g→a
(exon 22) |
PEO and tetraparesis
Severe childhood multi-system disorder |
Compound in trans with N468D
In severe childhood multi-system disorder found as compound with R227W |
Gonzalez - Vioque 2006: Not detected in 100 control subjects |
(Gonzalez - Vioque et al., 2006; de Vries et al., 2006) |
| R1187W |
3559 c→t
(exon 22) |
? |
Found in a patient with mitochondrial depletion syndrome and T cell immunodeficiency.
Pathogenesis unclear. |
Not detected in 100 Turkish control alleles |
(Reichenbach et al., 2006) |
| K1191N |
3573 g→t
(exon 22) |
Alpers |
Compound in trans with A467T |
Not found in 664 German controls |
(Horvath et al., 2006) |
| K1191R |
3572 a→g
(exon 22) |
Myocerebrohepatopathy |
In trans with T251I-P587L |
|
(Wong et al., 2008) |
| D1196N |
3586 g→a
(exon 22) |
|
Myopathy |
In trans w/ G517V |
(Wong et al., 2008) |
| G1205A |
3614 g→ c
(exon 22) |
|
Heterozygous w/ Retinitis pigmentosa, hearing loss, failure to thrive |
|
(Wong et al., 2008) |
| Y1210fs1216stop |
3630 ins c
(exon 22) |
Alpers |
Compound in trans with W748S - E1143G, Mutation causes frameshift to stop at a.a. 1225 |
|
(Ferrari et al., 2005) |
| S1230F |
3689 c→t |
Neutral polymorphism |
|
<1 % in control populations |
(Luoma et al., 2007) |
| Q1236H |
3708 g→t
(exon 22) |
Neutral polymorphism
Alpers |
Has also been found in PEO patients, and in ataxia - myopathy in cis with R627Q and in trans with A467T
Found in trans with A467T, and in cis w/ T849H. Also found as a compound w/ R1096C. |
4.0% of 450 individuals |
(GeneSNPs, 2004)
(Di Fonzo et al., 2003)
(Luoma et al., 2005)
(Wong et al., 2008) |
|