Answers to Missing Mtdna Found at Last RESEARCH NEWS

RESEARCH NEWS

Answers to Missing mtDNA Found at Last

Review of Mandel H, Szargel R, Labay V et al. 2001 The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 29:337–341 [Erratum: 2001 Nat Genet 29:491]; and Saada A, Shaag A, Mandel H et al. 2001 Mutant mitochondrial thymidine kinase in mitochondrial depletion myopathy. Nat Genet 29:342–344

RIMARY AND SECONDARY mitochon- oxycytidine, and deoxyuridine. Muta- ANNETTE FEIGENBAUM Pdrial DNA depletion syndromes tions in DGUOK will thus result in an (MDS) (OMIM 251880) are character- imbalance in the nucleotide pool and ized by a quantitative reduction in mi- red fibers or cardiac involvement. Bio- impaired mtDNA synthesis. tochondrial DNA (mtDNA) copy num- chemical analyses of the affected tis- Employing a genome-wide screen ber (1). The structure, size, and sues show nonspecific low activity of using homozygosity mapping strategy sequence of the mtDNA are normal. the mitochondrial respiratory chain the authors (2) identified linkage to the Many genes have been investigated as complexes I, III, IV, and V which have DGUOK gene on chromosome 2p13 candidates in primary MDS; none have mtDNA encoded subunits, relative to and a single base deletion segregating been consistently shown to be associ- complex II, which is entirely nuclear with the hepatocerebral form of MDS. ated with these conditions until the encoded. Southern blot analysis shows Saada et al. (3) described four families present papers. These articles (2, 3) a reduced mtDNA:nuclear DNA ratio with children affected with muscular report two genes – the gene for deox- (the deficient range is defined as less MDS and identify mutations in the yguanosine kinase (dGK) DGUOK in than 40% of mean control values) with TK2 gene on chromosome 16q22. Ͻ the hepatocerebral form, and the TK2 patients often showing 10%. They also describe the reduced activity gene for mitochondrial thymidine ki- The importance of the nucleoside of TK2 with deoxythymidine in the nase associated with myopathic form pools in mtDNA stability and mainte- affected muscle tissue mitochondria. nance were recognized with the dis- of MDS in some cases. This is a fas- Patients with depletion also have com- covery of the defects in thymidine cinating example of the defects in in- pensatory increase in activity of the phosphorylase in mitochondrial neuro- tergenomic communication, a defect in other nonmutated deoxynucleoside ki- gastrointestinal encephalomyopathy nuclear to mitochondrial DNA control. nases (3). More recently duplications, (MNGIE) syndrome (4) and adenine The mtDNA depletion is thus a distant deletions, and other missense point nucleotide translocator ANT1 in ad- effect of the primary enzyme defi- mutations have been described in PEO (5). The cytosolic and mitochon- ciency. This has already lead in some DGUOK and there is some preliminary drial nucleoside pools are balanced and cases to easier diagnostic tests in these essential even in non-replicating cells. evidence for possible genotype/pheno- conditions and to prenatal diagnostic There are no enzymes for nucleotide type correlation (6). possibilities, which were not previ- synthesis within the mitochondria - the Possible explanations for the differ- ously possible. pool thus depends on the salvage path- ing expression of these autosomally The MDS are clinically heteroge- way. Imbalance in these pools has inherited biochemical defects in differ- neous disorders that may affect multi- been associated with increased DNA ent patients and tissues have been dis- ple or single organ systems, e.g. liver damage. There are four human de- cussed. For DGUOK, possibilities in- and/or muscle and brain, and/or heart oxynucleoside kinases: TK1, TK2, clude the differing expression of and kidney. The hepatocerebral form dGK, and deoxycytidine kinase (dCK). deoxycytidine kinase (dCK) expres- can present with early infantile onset DGK and TK2 are essential enzymes sion, which, with overlapping phos- liver failure, jaundice, coagulopathy, in the intramitochondrial nucleotide phorylation function, could compen- hypoglycemia, lactic acidosis, and salvage pathway, which is the sole sate for a defect in dGK. However, raised alpha-fetoprotein. Characteristic source of nucleosides for mtDNA syn- dCK has very low expression in the histopathologic features include cho- thesis when cytosolic dNTP synthesis high energy requiring organs, brain, lestasis, fibrosis/cirrhosis, steatosis, is down regulated in non-replicating and liver. TK2 activity in muscle is and giant cell formation. These chil- cells. DGK phosphorylates deoxyade- low compared to other tissues so these dren may also have CNS neurodegen- nine and deoxyguanosine to the de- tissues, which are non-replicating and erative disease such as Leigh disease oxynucleotide monophosphates. TK2 therefore do not have active thymidine and/or muscular disease with ragged phosphorylates deoxythymidine, de- kinase I, may be more at risk of ex-

319 320 RESEARCH NEWS

pressing disease. There may also be involved in MDS and need further 5. Kaukonen J, Juselius JK, Tiranti V, Kyttala A, Zeviani M, Comi GP, Keranen S, Peltonen L, Suomalainen modifying effects of the deoxynucle- study. 2000 A Role of adenine nucleotide translocator 1 in otide carrier/s, which transport cytoso- mtDNA maintenance. Science 289(5480):782–785 6. Salviari L, Sacconi S, Mancuso M, Otaegui D, Ca- lic deoxynucleotides into the mito- 1. Moraes CT, Shanske S, Tritschler H-J, Aprille JR, man P, Marina A, Rabinowitz S, Schiffman R, chondrion across the impermeable Andreetta F, Bonilla E, Schon EA, DiMauro S 1991 Thompson K, Wilson C, Feigenbaum A, Naini A, mtDNA depletion with variable tissue expression: a Hirano M, Bonilla E, DiMauro S, Vu T 2002 Mito- inner mitochondrial membrane. All novel genetic abnormality in mitochondrial diseases. chondrial DNA Depletion and dGK gene mutations. Am J Hum Genet 48:492–501 Ann Neurol (in press) these possibilities need to be further 2. Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, investigated for us to have a better Shalata A, Anbinder Y, Berkowitz D, Hartman C, Barak M, Eriksson S, Cohen N 2001 The deox- understanding of the pathogenesis of yguanosine kinase gene is mutated in individuals these conditions. In addition, not all with depleted hepatocerebral mitochondrial DNA. Division of Clinical and Metabolic Genetics Nat Genet 29:337–341 patients with hepatic or muscular The Hospital for Sick Children 3. Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, 555 University Avenue mtDNA depletion have been found to Elpeleg O 2001 Mutant mitochondrial thymidine kinase in mitochondrial depletion myopathy. Nat Toronto Ontario have mutations in DGUOK or TK2 Genet 29:342–344 M5G 1X8 Canada indicating that other gene defects, per- 4. Nishino I, Spinazzola A, Hirano M 1999 Thymidine e-mail: [email protected] phosphorylase gene mutations in MNGIE, a human haps the other nucleotide kinases, are mitochondrial disorder. Science 283(5402):689–692 DOI: 10.1203/01.PDR.0000030705.04968.14