Clinical Phenotypes (non-LHON) Associated with mtDNA Polypeptide Gene Mutations Reported in the Literature
Syndromes |
Locus |
Disease* |
Allele |
Nucleotide Change |
AA Change |
Ho� |
He� |
Status** |
References |
Dystonia |
MTND1 |
Adult-Onset Dystonia |
A3796G |
A-G |
T164A |
- |
+ |
Prov |
(64) |
Dystonia,Leigh Syndrome |
MTND6 |
LS/Dystonia |
T14487C |
T-C |
M63V |
- |
+ |
Cfrm |
(65) |
Dystonia,Leigh Syndrome |
MTND6 |
LDYT/LS |
G14459A |
G-A |
A72V |
+ |
+ |
Cfrm |
(26), (32) |
Leigh Syndrome |
MTND3 |
LS |
T10158C |
T-C |
S34P |
- |
+ |
Cfrm |
(36) |
Leigh Syndrome |
MTND3 |
LS-like/ESOC |
T10191C |
T-C |
S45P |
- |
+ |
Cfrm |
(71) |
Leigh Syndrome |
MTND4 |
LS |
C11777A |
C-A |
R340S |
- |
+ |
Cfrm |
(19) |
Leigh Syndrome |
MTND5 |
LS |
T12706C |
T-C |
F124L |
- |
+ |
Cfrm |
(70) |
Leigh syndrome |
MTATP6 |
LS/FBSN |
T9176C |
T-C |
L217P |
+ |
+ |
Prov |
(73) |
Leigh Syndrome |
MTATP6 |
LS |
T9176G |
T-G |
L217R |
- |
+ |
Prov |
(10) |
Leigh Syndrome |
MTATP6 |
LS |
T9185C |
T-C |
L220P |
- |
+ |
Prov |
(45) |
Leigh Syndrome |
MTATP6 |
LS |
T9191C |
T-C |
L222P |
- |
+ |
Prov |
(45) |
Leigh Syndrome |
MTATP6 |
LS/NARP |
T8993C |
T-C |
L156P |
- |
+ |
Cfrm |
(11, 18, 41, 58) |
MTATP6
NARP |
T8993G |
T-G |
L156R |
- |
+ |
Cfrm |
(12, 24, 25, 47, 48, 51, 59, 63, 67, 68) |
Leigh Syndrome |
MTCO3 |
LS-like |
C9537insC |
C-CC |
Q111frameshift |
+ |
- |
Prov |
(74) |
|
Encephalomyopathy, MELAS |
MTND1 |
MELAS |
T3308C |
T-C |
M1T |
- |
+ |
Prov |
(9) |
Encephalomyopathy, MELAS |
MTND1 |
MELAS/LHON |
G3376A |
G-A |
E24K |
- |
+ |
Prov |
(6) |
Encephalomyopathy, MELAS |
MTND1 |
MELAS |
G3697A |
G-A |
G131S |
- |
+ |
Prov |
(33) |
Encephalomyopathy, MELAS |
MTND1 |
MELAS |
G3946A |
G-A |
E214K |
+ |
+ |
Prov |
(33) |
Encephalomyopathy, MELAS |
MTND1 |
MELAS |
T3949C |
T-C |
Y215H |
- |
+ |
Prov |
(33) |
Encephalomyopathy, MELAS |
MTND4 |
MELAS |
A11084G |
A-G |
T109A |
+ |
+ |
P.M. |
(38, 57) |
Encephalomyopathy, MELAS |
MTND5 |
MELAS |
A12770G |
A-G |
E145G |
- |
+ |
Prov |
(40) |
Encephalomyopathy, MELAS |
MTND5 |
MELAS/LHON/ LS overlap syndrome |
A13045C |
A-C |
M237L |
- |
+ |
Prov |
(40) |
Encephalomyopathy, MELAS |
MTND5 |
MELAS/LS |
A13084T |
A-T |
S250C |
- |
+ |
Prov |
(16) |
Encephalomyopathy, MELAS |
MTND5 |
MELAS/LS |
G13513A |
G-A |
D393N |
- |
+ |
Cfrm |
(60) |
Encephalomyopathy, MELAS |
MTND5 |
MELAS |
A13514G |
A-G |
D393G |
- |
+ |
Cfrm |
(15) |
Encephalomyopathy, MELAS |
MTND6 |
MELAS |
G14453A |
G-A |
A74V |
- |
+ |
Prov |
(54) |
Encephalomyopathy, MELAS |
MTCYB |
MELAS/PD |
14787del4 |
TTAA-del |
I14frameshift |
- |
+ |
Prov |
(17) |
Epilepsy |
MTCO1 |
Therapy-resistant Epilepsy |
C6489A |
C-A |
L196I |
- |
+ |
Prov |
(76) |
Encephalomyopathy, Multisystem Disorder |
MTCO1 |
Multisystem Disorder |
G6930A |
G-A |
G343Ter |
- |
+ |
Prov |
(7) |
Encephalomyopathy, Multisystem Disorder |
MTCOI |
Myopathy and Cortical Lesions |
6015del5 |
Del 5 bp |
Frameshift, 42 peptide |
- |
+ |
Prov |
(14) |
Encephalomyopathy |
MTCO2 |
Encephalomyopathy |
T7587C |
T-C |
M1T |
- |
+ |
Prov |
(13) |
Encephalomyopathy, Multisystem Disorder |
MTCO2 |
Multisystem Disorder |
G7896A |
G-A |
W104Ter |
- |
+ |
Prov |
(8) |
Encephalomyopathy, Lactic Acidosis |
MTCO2 |
Lactic Acidosis |
8042del2 |
AT-del |
M153Ter |
- |
+ |
Prov |
(81) |
Encephalomyopathy |
MTCO3 |
Encephalomyopathy |
G9952A |
G-A |
W248Ter |
- |
+ |
Prov |
(23) |
Encephalomyopathy, MELAS |
MTCO3 |
MELAS/PEM/ NAION |
T9957C |
T-C |
F251L |
- |
+ |
Prov |
(43) |
Encephalomyopathy, Lactic Acidosis |
MTATP6 |
Lactic Acidosis/ Seizures |
9205del2 |
TA-del |
Ter227M |
+ |
- |
Prov |
(72) |
Encephalomyopathy, Lactic Acidosis |
MTCYB |
Multisystem Disorder |
A15579G |
A-G |
Y278C |
- |
+ |
Prov |
(80) |
Encephalomyopathy, Septo-Optic Dysplasia |
MTCYB |
Septo-Optic Dysplasia |
T14849C |
T-C |
S35P |
- |
+ |
Prov |
(61) |
|
MM, Exercise Intolerance |
MTCYB |
EXIT |
G14846A |
G-A |
G34S |
- |
+ |
Prov |
(4) |
Mitochondrial Myopathy |
MTCYB |
MM |
G15059A |
G-A |
G190Ter |
- |
+ |
Prov |
(1) |
MM, Exercise Intolerance |
MTCYB |
EXIT |
G15084A |
G- A |
W113Ter |
- |
+ |
Prov |
(4) |
MM, Exercise Intolerance |
MTCYB |
EXIT |
G15150A |
G-A |
W135Ter |
- |
+ |
Prov |
(37) |
MM, Exercise Intolerance |
MTCYB |
EXIT |
G15168A |
G-A |
W141Ter |
- |
+ |
Prov |
(4) |
MM, Exercise Intolerance |
MTCYB |
EXIT |
T15197C |
T-C |
S151P |
- |
+ |
Prov |
(37) |
MM, Exercise Intolerance |
MTCYB |
EXIT/Encephalomyopathy |
G15242A |
G-A |
G166Ter |
- |
+ |
Prov |
(28, 31) |
MM, Exercise Intolerance |
MTCYB |
EXIT |
G15497A |
G-A |
G251S |
+ |
- |
Prov |
(66) |
MM, Exercise Intolerance |
MTCYB |
EXIT |
15498del24 |
24 bp deletion- |
251GDPDNYTL-del258 |
- |
+ |
Prov |
(4) |
MM, Exercise Intolerance |
MTCYB |
EXIT |
G15615A |
G-A |
G290D |
- |
+ |
Prov |
(20) |
MM, Exercise Intolerance |
MTCYB |
EXIT |
G15723A |
G-A |
W326Ter |
- |
+ |
Prov |
(4) |
Mitochondrial Myopathy |
MTCYB |
MM |
G15762A |
G-A |
G339E |
- |
+ |
Prov |
(2) |
MM, CPEO |
MTND4 |
CPEO |
T11232C |
T-C |
L140P |
- |
+ |
Prov |
(52) |
MM, Exercise Intolerance |
MTND4 |
EXIT |
G11832A |
G-A |
W358Ter |
- |
+ |
Prov |
(5) |
MM, Exercise Intolerance |
MTCO1 |
EXIT/Myoglobinuria |
G5920A |
G-A |
W6Ter |
- |
+ |
Prov |
(27) |
Mitochondrial Myopathy |
MTCO1 |
MM & Rhabdomyolysis |
G6708A |
G-A |
G269Ter |
- |
+ |
Prov |
(34) |
Mitochondrial Myopathy |
MTCO2 |
MM |
T7671A |
T-A |
M29K |
- |
+ |
Prov |
(53) |
MM, Exercise Intolerance |
MTCO2 |
EXIT/Rhabdomyolysis |
T7989C |
T-C |
L135P |
- |
+ |
Prov |
(44) |
Mitochondrial Myopathy |
MTCO3 |
Myopathy and Myoglobinuria |
9487del15 |
Del 15 bp |
Removed 5 aa |
|
+ |
Prov |
(29) |
|
Hypertrophic Cardiomyopathy |
MTCYB |
HCM |
G15243A |
G-A |
G166E |
- |
+ |
Prov |
(75) |
Hypertrophic Cardiomyopathy |
MTCYB |
HCM |
G15498A |
G-A |
G251D |
- |
+ |
Prov |
(3) |
|
Deafness |
MTCO1 |
DEAF |
A7443G |
A-G |
Ter514G |
+ |
- |
Prov |
(49) |
Deafness |
MTCO1 |
DEAF |
A7445C |
A-C |
Ter514S |
+ |
- |
Prov |
(49) |
Deafness-Sensory Neural Hearing Loss |
MTCO1 |
SNHL/LHON |
G7444A |
G-A |
Ter514K |
+ |
- |
Prov |
(49) |
Deafness-Sensory Neural Hearing Loss |
MTCO1 |
SNHL |
A7445G |
A-G |
Ter514Ter |
+ |
+ |
Cfrm |
(22, 55, 56, 77) |
Deafness-Sensory Neural Hearing Loss |
MTCO2 |
SNHL |
A8108G |
A-G |
I175V |
+ |
- |
Prov |
(79) |
Deafness-Sensory Neural Hearing Loss |
MTND6 |
SNHL |
C14340T |
C-T |
V112M |
+ |
- |
Prov |
(79) |
|
Diabetes Mellitus |
MTND1 |
NIDDM/PEO |
G3316A |
G- A |
A4T |
+ |
- |
Unclear |
(46) |
Diabetes Mellitus |
MTND4 |
DM |
A12026G |
A-G |
I423V |
+ |
- |
Prov |
(69) |
|
Alzheimer & Parkinson Disease |
MTND1 |
ADPD |
A3397G |
A-G |
M31V |
+ |
- |
Prov |
(62, 78) |
Alzheimer & Parkinson Disease |
MTND2 |
AD |
G5460A |
G-A |
A331T |
+ |
+ |
P.M. |
(35, 39, 50) |
Alzheimer & Parkinson Disease |
MTND2 |
AD |
G5460T |
G-T |
A331S |
+ |
+ |
Prov |
(35, 39, 50) |
|
Idiopathic Sideroblastic Anemia |
MTCO1 |
SIDA |
T6721C |
T-C |
M273T |
- |
+ |
Prov |
(21) |
Idiopathic Sideroblastic Anemia |
MTCO1 |
SIDA |
T6742C |
T-C |
I280T |
- |
+ |
Prov |
(21) |
|
Abbreviations
�
Plasmy: Ho, homoplasmy; He, heteroplasmy
*
Disease: AD, Alzheimer's Disease; ADPD, Alzheimer's Disease and Parkinsons's Disease; CPEO, Chronic Progressive External Ophthalmoplegia; EXIT, exercise intolerance; LHON Leber Hereditary Optic Neuropathy; LS, Leigh Syndrome; MELAS, Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes; MM, mitochondrial myopathy; NAION Nonarteritic Anterior Ischemic Optic Neuropathy; NARP, Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa; NIDDM, Non-Insulin Dependent Diabetes Mellitus; SIDA, sideroblastic anemia; SNHL, Sensorineural Hearing Loss.
* *Status: Cfrm, considered confirmed by multiple reports in the literature; Prov, provisional isolated report(s), not yet confirmed by multiple labs; P.M., reported originally in the literature at pathogenic but now generally considered to be a polymorphic variant.
References
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33. Kirby, D. M.,
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38. Lertrit, P., Noer, A. S., Jean-Francois, M. J., Kapsa, R., Dennett, X., Thyagarajan, D., Lethlean, K., Byrne, E. and Marzuki, S. (1992).
"A new disease-related mutation for mitochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respiratory complex I." American Journal of Human Genetics 51(3):457-468.
39. Lin, F., Lin, R., Wisniewski, H. M., Hwang, Y., Grundke-Iqbal, I., Healy- Louie, G. and Iqbal, K. (1992).
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40. Liolitsa, D., Rahman, S., Benton, S., Carr, L. J. and Hanna, M. G. (2003).
"Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations?" Annals of Neurology 53(1):128-132.
41. Mak, S. C., Chi, C. S. and Tsai, C. R. (1998).
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42. Manfredi, G., Bonilla, E., Schon, E. A.,
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43. Manfredi, G., Schon, E. A., Moraes, C. T., Bonilla, E., Berry, G. T., Sladky, J. T. and
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45. Moslemi, A. R., Darin, N., Tulinius, M., Oldfors, A. and Holme, E. (2005).
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46. Nakagawa, Y., Ikegami, H., Yamato, E., Takekawa, K., Fujisawa, T., Hamada, Y., Ueda, H., Uchigata, Y., Miki, T., Kumahara, Y. and Ogihara, T. (1995).
"A new mitochondrial DNA mutation associated with non-insulin-dependent diabetes mellitus [published erratum appears in Biochem Biophys Res Commun 1995;212(2):718]." Biochemical and Biophysical Research Communications 209(2):664-668.
47. Obayashi, T., Hattori, K., Sugiyama, S., Tanaka, M., Tanaka, T., Itoyama, S., Deguchi, H., Kawamura, K., Koga, Y., Toshima, H., Takeda, N., Nagano, M., Ito, T. and Ozawa, T. (1992).
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48. Ortiz, R. G., Newman, N. J., Shoffner, J. M., Kaufman, A. E., Koontz, D. A. and Wallace, D. C. (1993).
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49. Pandya, A., Xia, X. J., Erdenetungalag, R., Amendola, M., Landa, B., Radnaabazar, J., Dangaasuren, B., Van Tuyle, G. and Nance, W. E. (1999).
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50. Petruzzella, V., Chen, X. and Schon, E. A. (1992).
"Is a point mutation in the mitochondrial ND2 gene associated with Alzheimer's disease?" Biochemical and Biophysical Research Communications 186(1):491-497.
51. Puddu, P., Barboni, P., Mantovani, V., Montagna, P., Cerullo, A., Bragliani, M., Molinotti, C. and Caramazza, R. (1993).
"Retinitis pigmentosa, ataxia, and mental retardation associated with mitochondrial DNA mutation in an Italian family." British Journal of Ophthalmology 77(2):84-88.
52. Pulkes, T., Liolitsa, D., Nelson, I. P. and Hanna, M. G. (2003).
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53. Rahman, S., Taanman, J. W., Cooper, J. M., Nelson, I., Hargreaves, I., Meunier, B., Hanna, M. G., Garcia, J. J., Capaldi, R. A., Lake, B. D., Leonard, J. V. and Schapira, A. H. (1999).
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54. Ravn, K., Wibrand, F., Hansen, F. J., Horn, N., Rosenberg, T. and Schwartz, M. (2001).
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55. Reid, F. M., Vernham, G. A. and Jacobs, H. T. (1994).
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56. Reid, F. M., Vernham, G. A. and Jacobs, H. T. (1994).
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57. Sakuta, R., Goto, Y., Nonaka, I. and Horai, S. (1993).
"An A-to-G transition at nucleotide pair 11084 in the ND4 gene may be an mtDNA polymorphism." American Journal of Human Genetics 53(4):964-965.
58. Santorelli, F. M., Shanske, S., Jain, K. D., Tick, D., Schon, E. A. and
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59. Santorelli, F. M., Shanske, S., Macaya, A.,
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60. Santorelli, F. M., Tanji, K., Kulikova, R., Shanske, S., Vilarinho, L., Hays, A. P. and
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61. Schuelke, M., Krude, H., Finckh, B., Mayatepek, E., Janssen, A., Schmelz, M., Trefz, F., Trijbels, F. and Smeitink, J. (2002).
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62. Shoffner, J. M., Brown, M. D., Torroni, A., Lott, M. T., Cabell, M. R., Mirra, S. S., Beal, M. F., Yang, C., Gearing, M., Salvo, R., Watts, R. L., Juncos, J. L., Hansen, L. A., Crain, B. J., Fayad, M., Reckord, C. L. and Wallace, D. C. (1993).
"Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients." Genomics 17(1):171-184.
63. Shoffner, J. M., Fernhoff, M. D., Krawiecki, N. S., Caplan, D. B., Holt, P. J., Koontz, D. A., Takei, Y., Newman, N. J., Ortiz, R. G., Polak, M., Ballinger, S. W., Lott, M. T. and Wallace, D. C. (1992).
"Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation." Neurology 42(11):2168-2174.
64. Simon, D. K., Friedman, J., Breakefield, X. O., Jankovic, J., Brin, M. F., Provias, J., Bressman, S. B., Charness, M. E., Tarsy, D., Johns, D. R. and Tarnopolsky, M. A. (2003).
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65. Solano, A., Roig, M., Vives-Bauza, C., Hernandez-Pena, J., Garcia-Arumi, E., Playan, A., Lopez-Perez, M. J., Andreu, A. L. and Montoya, J. (2003).
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66. Tarnopolsky, M. A., Simon, D. K., Roy, B. D., Chorneyko, K., Lowther, S. A., Johns, D. R., Sandhu, J. K., Li, Y. and Sikorska, M. (2004).
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67. Tatuch, Y., Christodoulou, J., Feigenbaum, A., Clarke, J. T. R., Wherret, J., Smith, C., Rudd, N., Petrova-Benedict, R. and Robinson, B. H. (1992).
"Heteroplasmic mtDNA mutation (T-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high." American Journal of Human Genetics 50(4):852-858.
68. Tatuch, Y. and Robinson, B. H. (1993).
"The mitochondrial DNA mutation at 8993 associated with NARP slows the rate of ATP synthesis in isolated lymphoblast mitochondria." Biochemical and Biophysical Research Communications 192:124-128.
69. Tawata, M., Ohtaka, M., Iwase, E., Ikegishi, Y., Aida, K. and Onaya, T. (1998).
"New mitochondrial DNA homoplasmic mutations associated with Japanese patients with type 2 diabetes." Diabetes 47(2):276-277.
70. Taylor, R. W., Morris, A. A., Hutchinson, M. and Turnbull, D. M. (2002).
"Leigh disease associated with a novel mitochondrial DNA ND5 mutation." European Journal of Human Genetics 10(2):141-144.
71. Taylor, R. W., Singh-Kler, R., Hayes, C. M., Smith, P. E. and Turnbull, D. M. (2001).
"Progressive mitochondrial disease resulting from a novel missense mutation in the mitochondrial DNA ND3 gene." Annals of Neurology 50(1):104-107.
72. Temperley, R. J., Seneca, S. H., Tonska, K., Bartnik, E., Bindoff, L. A., Lightowlers, R. N. and Chrzanowska-Lightowlers, Z. M. (2003).
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73. Thyagarajan, D., Shanske, S., Vazquez-Memije, M., De Vivo, D. and
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"A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis." Annals of Neurology 38(3):468-472.
74. Tiranti, V., Corona, P., Greco, M., Taanman, J. W., Carrara, F., Lamantea, E., Nijtmans, L., Uziel, G. and Zeviani, M. (2000).
"A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome." Human Molecular Genetics 9(18):2733-2742.
75 . Valnot, I., Kassis, J., Chretien, D., de Lonlay, P., Parfait, B., Munnich, A., Kachaner, J., Rustin, P. and Rotig, A. (1999).
"A mitochondrial cytochrome b mutation but no mutations of nuclearly encoded subunits in ubiquinol cytochrome c reductase (complex III) deficiency." Human Genetics 104(6):460-466.
76. Varlamov, D. A., Kudin, A. P., Vielhaber, S., Schroder, R., Sassen, R., Becker, A., Kunz, D., Haug, K., Rebstock, J., Heils, A., Elger, C. E. and Kunz, W. S. (2002).
"Metabolic consequences of a novel missense mutation of the mtDNA CO I gene." Human Molecular Genetics 11(16):1797-1805.
77. Vernham, G. A., Reid, F. M., Rundle, P. A. and Jacobs, H. T. (1994).
"Bilateral sensorineural hearing loss in members of a maternal lineage with mitochondrial point mutation." Clinical Otolaryngology 19(4):314-319.
78. Wallace, D. C., Shoffner, J. M., Brown, M. D., Torroni, A., Lott, M. T. and Cabell, M. (1992). "Mitochondrial DNA mutations associated with Alzheimer's and Parkinson's disease." American Journal of Human Genetics 51:A30.
79. Wang, Q., Li, R., Zhao, H., Peters, J. L., Liu, Q., Yang, L., Han, D., Greinwald, J. H., Jr., Young, W. Y. and Guan, M. X. (2005).
"Clinical and molecular characterization of a Chinese patient with auditory neuropathy associated with mitochondrial 12S rRNA T1095C mutation." American Journal of Medical Genetics 133A(1):27-30.
80. Wibrand, F., Ravn, K., Schwartz, M., Rosenberg, T., Horn, N. and Vissing, J. (2001).
"Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene." Annals of Neurology 50(4):540-543.
81. Wong, L. J., Dai, P., Tan, D., Lipson, M., Grix, A., Sifry-Platt, M., Gropman, A. and Chen, T. J. (2001).
"Severe lactic acidosis caused by a novel frame-shift mutation in mitochondrial-encoded cytochrome c oxidase subunit II." American Journal of Medical Genetics 102(1):95-99.
This table is reproduced with permission from PRINCIPLES AND PRACTICE OF MEDICAL GENETICS, 5/e. � 2006 Elsevier Ltd.