Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy

被引:455
作者
Saada, A
Shaag, A
Mandel, H
Nevo, Y
Eriksson, S
Elpeleg, O [1 ]
机构
[1] Hebrew Univ Jerusalem, Fac Med, Shaare Zedek Med Ctr, Metab Dis Unit, IL-91031 Jerusalem, Israel
[2] Rambam Med Ctr, Dept Pediat, IL-31096 Haifa, Israel
[3] Tel Aviv Sourasky Med Ctr, Pediat Neurol Unit, IL-65211 Tel Aviv, Israel
[4] Swedish Univ Agr Sci, Dept Vet Med Chem, SE-75123 Uppsala, Sweden
关键词
D O I
10.1038/ng751
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The mitochondrial deoxyribonucleotide (dNTP) pool is separated from the cytosolic pool because the mitochondria inner membrane is impermeable to charged molecules. The mitochondrial pool is maintained by either import of cytosolic dNTPs through dedicated transporters(1,2) or by salvaging deoxynucleasides within the mitochondria; apparently, enzymes of the de novo dNTP synthesis pathway are not present in the mitochondria. In non-replicating cells, where cytosolic dNTP synthesis is downregulated, mtDNA synthesis depends solely on the mitochondrial salvage pathway enzymes, the deoxyribonucleosides kinases. Two of the four human deoxyribonucleoside kinases, deoxyguanosine kinase (dGK) and thymidine kinase-2 (TK2), are expressed in mitochondria(3-6). Human dGK efficiently phosphorylates deoxyguanosine and deoxyadenosine, whereas TK2 phosphorylates deoxythymidine, deoxycytidine and deoxyuridine. Here we identify two mutations in TK2, histidine 90 to asparagine and isoleucine 181 to asparagine, in four individuals who developed devastating myopathy and depletion of muscular mitochondrial DNA in infancy. In these individuals, the activity of TK2 in muscle mitochondria is reduced to 14-45% of the mean value in healthy control individuals. Mutations in TK2 represent a new etiology for mitochondrial DNA depletion, underscoring the importance of the mitochondrial dNTP pool in the pathogenesis of mitochondrial depletion.
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页码:342 / 344
页数:3
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