Neurology 2002;59:1197-1202
© 2002 American Academy of Neurology
Mitochondrial DNA depletion
Mutations in thymidine kinase gene with myopathy and SMA
M. Mancuso, MD,
L. Salviati, MD,
S. Sacconi, MD,
D. Otaegui,
P. Camaño,
A. Marina, PhD,
S. Bacman, MD,
C.T. Moraes, MD,
J.R. Carlo, MD,
M. Garcia, MD,
M. Garcia-Alvarez, MD,
L. Monzon,
A.B. Naini, PhD,
M. Hirano, MD,
E. Bonilla, MD,
A.L. Taratuto, MD,
S. DiMauro, MD and
T.H. Vu, MD
From the Departments of Neurology (Drs. Mancuso, Salviati, Sacconi, Naini, Hirano, Bonilla, DiMauro, and Vu, and D. Otaegui, P. Camaño, and L. Monzon) and Biochemistry and Molecular Biophysics (Dr. Marina), Columbia University, College of Physicians and Surgeons, New York, NY; Department of Neurosciences (Dr. Mancuso), University of Pisa, Italy; Department of Pediatrics (Dr. Salviati), University of Padova, Italy; Department of Neurology (Dr. Sacconi), University of Modena, Italy; University of Miami School of Medicine (Drs. Bacman and Moraes), Miami, FL; Clinicas Las Americas (Drs. Carlo and Garcia), San Juan, Puerto Rico; and Pediatric Neurology Department (Drs. Garcia-Alvarez and Taratuto), FLENI, Buenos Aires, Argentina.
Address correspondence and reprint requests to Dr. Tuan H. Vu, Department of Neurology, P&S Building 5-431, Columbia University, New York, NY 10032; e-mail: thv3{at}aol.com
Background: The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder of early childhood characterized by decreased mtDNA copy number in affected tissues. Recently, MDS has been linked to mutations in two genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2) and deoxy-guanosine kinase (dGK). Mutations in TK2 have been associated with the myopathic form of MDS, and mutations in dGK with the hepatoencephalopathic form.
Objectives: To further characterize the frequency and clinical spectrum of these mutations, the authors screened 20 patients with myopathic MDS.
Results: No patient had dGK gene mutations, but four patients from two families had TK2 mutations. Two siblings were compound heterozygous for a previously reported H90N mutation and a novel T77M mutation. The other siblings harbored a homozygous I22M mutation, and one of them had evidence of lower motor neuron disease. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28% to 37% of controls).
Conclusions: These results show that the clinical expression of TK2 mutations is not limited to myopathy and that the myopathic form of MDS is genetically heterogeneous.
This article has been cited by other articles:
|
|
|
|
 
S Rahman and M G Hanna
Diagnosis and therapy in neuromuscular disorders: diagnosis and new treatments in mitochondrial diseases
J. Neurol. Neurosurg. Psychiatry,
September 1, 2009;
80(9):
943 - 953.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Balzarini, I. Van Daele, A. Negri, N. Solaroli, A. Karlsson, S. Liekens, F. Gago, and S. Van Calenbergh
Human Mitochondrial Thymidine Kinase Is Selectively Inhibited by 3'-Thiourea Derivatives of {beta}-Thymidine: Identification of Residues Crucial for Both Inhibition and Catalytic Activity
Mol. Pharmacol.,
May 1, 2009;
75(5):
1127 - 1136.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Gotz, P. Isohanni, H. Pihko, A. Paetau, R. Herva, O. Saarenpaa-Heikkila, L. Valanne, S. Marjavaara, and A. Suomalainen
Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome
Brain,
November 1, 2008;
131(11):
2841 - 2850.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. O. Akman, B. Dorado, L. C. Lopez, A. Garcia-Cazorla, M. R. Vila, L. M. Tanabe, W. T. Dauer, E. Bonilla, K. Tanji, and M. Hirano
Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance
Hum. Mol. Genet.,
August 15, 2008;
17(16):
2433 - 2440.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Hirano, C. Angelini, P. Montagna, A. P. Hays, K. Tanji, H. Mitsumoto, P. H. Gordon, A. B. Naini, S. DiMauro, and L. P. Rowland
Amyotrophic Lateral Sclerosis With Ragged-Red Fibers
Arch Neurol,
March 1, 2008;
65(3):
403 - 406.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Amthor, R. Macharia, R. Navarrete, M. Schuelke, S. C. Brown, A. Otto, T. Voit, F. Muntoni, G. Vrbova, T. Partridge, et al.
Lack of myostatin results in excessive muscle growth but impaired force generation
PNAS,
February 6, 2007;
104(6):
1835 - 1840.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Oskoui, G. Davidzon, J. Pascual, R. Erazo, J. Gurgel-Giannetti, S. Krishna, E. Bonilla, D. C. De Vivo, S. Shanske, and S. DiMauro
Clinical Spectrum of Mitochondrial DNA Depletion Due to Mutations in the Thymidine Kinase 2 Gene.
Arch Neurol,
August 1, 2006;
63(8):
1122 - 1126.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Freisinger, N. Futterer, E. Lankes, K. Gempel, T. M. Berger, J. Spalinger, A. Hoerbe, C. Schwantes, M. Lindner, R. Santer, et al.
Hepatocerebral Mitochondrial DNA Depletion Syndrome Caused by Deoxyguanosine Kinase (DGUOK) Mutations.
Arch Neurol,
August 1, 2006;
63(8):
1129 - 1134.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. E. Durham, E. Bonilla, D. C. Samuels, S. DiMauro, and P. F. Chinnery
Mitochondrial DNA copy number threshold in mtDNA depletion myopathy
Neurology,
August 9, 2005;
65(3):
453 - 455.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mancuso, S. Ferraris, J. Pancrudo, A. Feigenbaum, J. Raiman, J. Christodoulou, D. R. Thorburn, and S. DiMauro
New DGK Gene Mutations in the Hepatocerebral Form of Mitochondrial DNA Depletion Syndrome
Arch Neurol,
May 1, 2005;
62(5):
745 - 747.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Ferrari, E. Lamantea, A. Donati, M. Filosto, E. Briem, F. Carrara, R. Parini, A. Simonati, R. Santer, and M. Zeviani
Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-{gamma}A
Brain,
April 1, 2005;
128(4):
723 - 731.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mancuso, M. Filosto, S. Tsujino, C. Lamperti, S. Shanske, M. Coquet, C. Desnuelle, and S. DiMauro
Muscle Glycogenosis and Mitochondrial Hepatopathy in an Infant With Mutations in Both the Myophosphorylase and Deoxyguanosine Kinase Genes
Arch Neurol,
October 1, 2003;
60(10):
1445 - 1447.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-W. Taanman, J. R. Muddle, and A. C. Muntau
Mitochondrial DNA depletion can be prevented by dGMP and dAMP supplementation in a resting culture of deoxyguanosine kinase-deficient fibroblasts
Hum. Mol. Genet.,
August 1, 2003;
12(15):
1839 - 1845.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mancuso, M. Filosto, E. Bonilla, M. Hirano, S. Shanske, T. H. Vu, and S. DiMauro
Mitochondrial Myopathy of Childhood Associated With Mitochondrial DNA Depletion and a Homozygous Mutation (T77M) in the TK2 Gene
Arch Neurol,
July 1, 2003;
60(7):
1007 - 1009.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.R. Vila, T. Segovia-Silvestre, J. Gamez, A. Marina, A.B. Naini, A. Meseguer, A. Lombes, E. Bonilla, S. DiMauro, M. Hirano, et al.
Reversion of mtDNA depletion in a patient with TK2 deficiency
Neurology,
April 8, 2003;
60(7):
1203 - 1205.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Wang, A. Saada, and S. Eriksson
Kinetic Properties of Mutant Human Thymidine Kinase 2 Suggest a Mechanism for Mitochondrial DNA Depletion Myopathy
J. Biol. Chem.,
February 21, 2003;
278(9):
6963 - 6968.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
