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Human Molecular Genetics Advance Access originally published online on May 8, 2008
Human Molecular Genetics 2008 17(16):2433-2440; doi:10.1093/hmg/ddn143
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance

Hasan O. Akman1,{dagger}, Beatriz Dorado1,{dagger}, Luis C. López1, Ángeles García-Cazorla1,2, Maya R. Vilà1,3, Lauren M. Tanabe4, William T. Dauer1,4, Eduardo Bonilla1,5, Kurenai Tanji5 and Michio Hirano1,*

1 Department of Neurology 2 Department of Pharmacology 3 Department of Pathology, Columbia University Medical Center, New York, NY, USA 4 Department of Neurology, Hospital Sant Joan de Deu and CIBER-ER, Instituto de Salud Carlos III, Barcelona, Spain 5 Centre d’Investigacions en Bioquímica i Biología Molecular (CIBBIM), Hospital Universitari Vall d’Hebron, Barcelona, Spain

* To whom correspondence should be addressed at: Columbia University Medical Center, 1150 St Nicholas Ave., Russ Berrie Medical Pavilion, Room 317 New York, NY 10032, USA. Tel: +1 2123051048; Fax: +1 2123053986; Email: mh29{at}columbia.edu

Received April 9, 2008; Accepted May 6, 2008

Mitochondrial DNA (mtDNA) depletion syndrome (MDS), an autosomal recessive condition, is characterized by variable organ involvement with decreased mtDNA copy number and activities of respiratory chain enzymes in affected tissues. MtDNA depletion has been associated with mutations in nine autosomal genes, including thymidine kinase (TK2), which encodes a ubiquitous mitochondrial protein. To study the pathogenesis of TK2-deficiency, we generated mice harboring an H126N Tk2 mutation. Homozygous Tk2 mutant (Tk2–/–) mice developed rapidly progressive weakness after age 10 days and died between ages 2 and 3 weeks. Tk2–/– animals showed Tk2 deficiency, unbalanced dNTP pools, mtDNA depletion and defects of respiratory chain enzymes containing mtDNA-encoded subunits that were most prominent in the central nervous system. Histopathology revealed an encephalomyelopathy with prominent vacuolar changes in the anterior horn of the spinal cord. The H126N TK2 mouse is the first knock-in animal model of human MDS and demonstrates that the severity of TK2 deficiency in tissues may determine the organ-specific phenotype.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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