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Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them


Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy—the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk (i.e., those having low mutant mtDNA load) can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders.


Vyšlo v časopise: Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them. PLoS Genet 6(8): e32767. doi:10.1371/journal.pgen.1001066
Kategorie: Review
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001066

Souhrn

Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy—the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk (i.e., those having low mutant mtDNA load) can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders.


Zdroje

1. ManwaringN

JonesMM

WangJJ

RochtchinaE

HowardC

2007 Population prevalence of the MELAS A3243G mutation. Mitochondrion 7 230 233

2. van den OuwelandJM

LemkesHH

RuitenbeekW

SandkuijlLA

de VijlderMF

1992 Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet 1 368 371

3. WallaceDC

SinghG

LottMT

HodgeJA

SchurrTG

1988 Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242 1427 1430

4. PoultonJ

TurnbullDM

2000 74th ENMC international workshop: mitochondrial diseases 19-20 november 1999, Naarden, The Netherlands. Neuromuscul Disord 10 460 462

5. ThorburnD

WiltonL

Stock-MyerS

2009 Healthy baby girl born following pre-implantation Genetic diagnosis for mitochondrial DNA m.8993t>g Mutation. Mol Genet Metab 98 5 6

6. PoultonJ

BredenoordAL

2010 174th ENMC International workshop: applying pre-implantation genetic diagnosis to mtDNA diseases: implications of scientific advances 19-21 March 2010, Naarden, The Netherlands. Neuromuscul Disord, in press

7. CravenL

TuppenHA

GreggainsGD

HarbottleSJ

MurphyJL

2010 Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 465 82 85

8. TachibanaM

SparmanM

SritanaudomchaiH

MaH

ClepperL

2009 Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 461 367 372

9. PoultonJ

MarchingtonD

1997 Prospects for DNA-based Prenatal Diagnosis of Mitochondrial Disorders. Prenat Diagn 16 1247 1256

10. BouchetC

SteffannJ

CorcosJ

MonnotS

PaquisV

2006 Prenatal diagnosis of MELAS syndrome: contribution to understanding mitochondrial DNA segregation during human embryo fetal development. J Med Genet 43 788 792

11. SacconiS

SalviatiL

NishigakiY

WalkerWF

Hernandez-RosaE

2008 A functionally dominant mitochondrial DNA mutation. Hum Mol Genet 17 1814 1820

12. BlackGC

MortenK

LabordeA

PoultonJ

1996 Leber's hereditary optic neuropathy: heteroplasmy is likely to be significant in the expression of LHON in families with the 3460 ND1 mutation. Br J Ophthalmol 80 915 917

13. RahmanS

PoultonJ

MarchingtonD

SuomalainenA

2001 Decrease of 3243 A->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am J Hum Genet 68 238 240

14. LarssonNG

HolmeE

KristianssonB

OldforsA

TuliniusM

1990 Progressive increase of the mutated mitochondrial DNA fraction in Kearns-Sayre syndrome. Pediatr Res 28 131 136

15. WhiteS

ShanskeS

McGillJ

MountainH

GeraghtyM

1999 Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue- or age-related variation. J Inherit Metab Dis 22 899 914

16. RajasimhaHK

ChinneryPF

SamuelsDC

2008 Selection against Pathogenic mtDNA Mutations in a Stem Cell Population Leads to the Loss of the 3243A->G Mutation in Blood. Am J Hum Genet 82 333 343

17. PoultonJ

O'RahillyS

MortenK

ClarkA

1995 Mitochondrial DNA, diabetes and pancreatic pathology in Kearns-Sayre syndrome. Diabetologia 38 868 871

18. WeberK

WilsonJN

TaylorL

BrierleyE

JohnsonMA

1997 A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle. Am J Hum Genet 60 373 380

19. GrossNJ

GetzGS

RabinowitzM

1969 Apparent turnover of mitochondrial deoxyribonucleic acid and mitochondrial phospholipids in the tissues of the rat. J Biol Chem 244 1552 1562

20. WeberK

WilsonJ

TaylorL

BrierleyE

JohnsonM

1997 A New mtDNA mutation showing accumulation with time and restriction to skeletal muscle. Am J Hum Genet 60 373 380

21. PyleA

TaylorRW

DurhamSE

DeschauerM

SchaeferAM

2007 Depletion of mitochondrial DNA in leukocytes harboring the 3243A->G mtDNA mutation. J Med Genet 44 69 74

22. JenuthJ

PetersonA

ShoubridgeE

1997 Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nat Genet 16 93 95

23. SteffannJ

FrydmanN

GigarelN

BurletP

RayPF

2006 Analysis of mtDNA variant segregation during early human embryonic development: a tool for successful NARP preimplantation diagnosis. J Med Genet 43 244 247

24. MarchingtonD

PoultonJ

SellerA

HoltI

1996 Do sequence variants in the major non-coding region of the mitochondrial genome influence mitochondrial mutations associated with disease. Hum Mol Genet 5 473 479

25. MarchingtonD

HartshorneG

BarlowD

PoultonJ

1997 Homopolymeric tract heteroplasmy in mtDNA from tissues and single oocytes: support for a genetic bottleneck. Am J Hum Genet 60 408 416

26. ChinneryPF

SamuelsDC

1999 Relaxed replication of mtDNA: A model with implications for the expression of disease. Am J Hum Genet 64 1158 1165

27. HayashiJ

OhtaS

KikuchiA

TakemitsuM

GotoY

1991 Introduction of disease related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction. Proc Natl Acad Sci U S A 88 10614 10618

28. YonedaM

ChomynA

MartinuzziA

HurkoO

AttardiG

1992 Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy. Proc Natl Acad Sci U S A 89 11164 11168

29. DunbarD

MoonieP

JacobsH

HoltI

1995 Different cellular backgrounds confer a marked advantage to either mutant or wild-type mitochondrial genomes. Proc Natl Acad Sci U S A 92 6562 6566

30. BlokR

CookD

ThorburnD

DahlH

1997 Skewed segregation of the mtDNA nt 8993 (T->G) mutation in human ocytes. Am J Hum Genet 60 1495 1501

31. Vergani LRR

BrierleyCH

HannaM

HoltIJ

1999 Introduction of heteroplasmic mitochondrial DNA (mtDNA) from a patient with NARP into two human rho degrees cell lines is associated either with selection and maintenance of NARP mutant mtDNA or failure to maintain mtDNA. Hum Mol Genet 8 1751 1755

32. BattersbyBJ

Loredo-OstiJC

ShoubridgeEA

2003 Nuclear genetic control of mitochondrial DNA segregation. Nat Genet 33 183 186

33. BattersbyBJ

ShoubridgeEA

2001 Selection of a mtDNA sequence variant in hepatocytes of heteroplasmic mice is not due to differences in respiratory chain function or efficiency of replication. Hum Mol Genet 10 2469 2479

34. Moreno-LoshuertosR

Acin-PerezR

Fernandez-SilvaP

MovillaN

Perez-MartosA

2006 Differences in reactive oxygen species production explain the phenotypes associated with common mouse mitochondrial DNA variants. Nat Genet 38 1261 1268

35. LehtinenSK

HanceN

El MezianeA

JuholaMK

JuholaKM

2000 Genotypic stability, segregation and selection in heteroplasmic human cell lines containing np 3243 mutant mtDNA. Genetics 154 363 380

36. ChenH

ChanDC

2009 Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum Mol Genet 18 R169 176

37. EmmersonCF

BrownGK

PoultonJ

2001 Synthesis of mitochondrial DNA in permeabilised human cultured cells. Nucleic Acids Res 29 E1

38. HyvarinenAK

PohjoismakiJL

ReyesA

WanrooijS

YasukawaT

2007 The mitochondrial transcription termination factor mTERF modulates replication pausing in human mitochondrial DNA. Nucleic Acids Res 35 6458 6474

39. HessJF

ParisiMA

BennettJL

ClaytonDA

1991 Impairment of mitochondrial transcription termination by a point mutation associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 351 236 239

40. PoultonJ

1995 Transmission of mtDNA: Cracks in the bottleneck. Am J Hum Genet 57 224 226

41. PoultonJ

MarchingtonD

MacaulayV

1998 Is the bottleneck cracked? Am J Hum Genet 62 752 757

42. OlivoPD

Van de WalleMJ

LaipisPJ

HauswirthWW

1983 Nucleotide sequence evidence for rapid genotypic shifts in the bovine mitochondrial DNA D-loop. Nature 306 400 402

43. LaipisP

HauswirthW

O'BrianT

MichaelsG

1988 Unequal partitioning of bovine mitochondrial genotypes among siblings. Proc Natl Acad Sci U S A 85 8107 8110

44. AshleyC

LaipisP

HauswirthW

1989 Rapid sequestration of heteroplasmic bovine mitochondria. Nucleic Acids Res 17 7325 7331

45. AikenCE

Cindrova-DaviesT

JohnsonMH

2008 Variations in mouse mitochondrial DNA copy number from fertilization to birth are associated with oxidative stress. Reprod Biomed Online 17 806 813

46. PikoL

TaylorKD

1987 Amounts of mitochondrial DNA and abundance of some mitochondrial gene transcripts in early mouse embryos. Dev Biol 123 364 374

47. McConnellM

PetrieL

2004 Mitochondrial DNA turnover occurs during preimplantation development and can be modulated by environmental factors. Reprod Biomed Online 9 418 424

48. ThundathilJ

FilionF

SmithLC

2005 Molecular control of mitochondrial function in preimplantation mouse embryos. Mol Reprod Dev 71 405 413

49. CreeLM

SamuelsDC

de Sousa LopesSC

RajasimhaHK

WonnapinijP

2008 A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat Genet 40 249 254

50. CaoL

ShitaraH

HoriiT

NagaoY

ImaiH

2007 The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells. Nat Genet 39 386 390

51. CaoL

ShitaraH

SugimotoM

HayashiJ

AbeK

2009 New evidence confirms that the mitochondrial bottleneck is generated without reduction of mitochondrial DNA content in early primordial germ cells of mice. PLoS Genet 5 e1000756 doi:10.1371/journal.pgen.1000756

52. WaiT

TeoliD

ShoubridgeEA

2008 The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes. Nat Genet 40 1484 1488

53. JenuthJ

PetersonA

FuK

ShoubridgeE

1996 Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nat Genet 14 146 151

54. PoultonJ

MacaulayV

MarchingtonD

2003 Transmission, genetic counselling and prenatal diagnosis of mitochondrial DNA disease.

HoltI

Genetics of Mitochondrial Disease Oxford Oxford University Press 309 326

55. WonnapinijP

ChinneryPF

SamuelsDC

2010 Previous Estimates of Mitochondrial DNA Mutation Level Variance Did Not Account for Sampling Error: Comparing the mtDNA Genetic Bottleneck in Mice and Humans. Am J Hum Genet 86 1 11

56. SamuelsDC

WonnapinijP

CreeLM

ChinneryPF

2010 Reassessing evidence for a postnatal mitochondrial genetic bottleneck. Nat Genet 42 471 472

57. IborraFJ

KimuraH

CookPR

2004 The functional organization of mitochondrial genomes in human cells. BMC Biol 2 9

58. InoueK

NakadaK

OguraA

IsobeK

GotoY

2000 Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nat Genet 26 176 181

59. SatoA

NakadaK

ShitaraH

KasaharaA

YonekawaH

2007 Deletion-mutant mtDNA increases in somatic tissues but decreases in female germ cells with age. Genetics 177 2031 2037

60. ChinneryPF

DiMauroS

ShanskeS

SchonEA

ZevianiM

2004 Risk of developing a mitochondrial DNA deletion disorder. Lancet 364 592 596

61. PoultonJ

HoltI

1994 Mitochondrial DNA: does more lead to less? Nat Genet 8 313 315

62. StewartJB

FreyerC

ElsonJL

WredenbergA

CansuZ

2008 Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol 6 e10 doi:10.1371/journal.pbio.0060010

63. FanW

WaymireKG

NarulaN

LiP

RocherC

2008 A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319 958 962

64. MarchingtonDR

MacaulayV

HartshorneGM

BarlowD

PoultonJ

1998 Evidence from human oocytes for a genetic bottleneck in an mtDNA disease. Am J Hum Genet 63 769 775

65. Brown DTSD

MichaelEM

TurnbullDM

ChinneryPF

2001 Random genetic drift determines the level of mutant mtDNA in human primary oocytes. Am J Hum Genet 68 533 536

66. WonnapinijP

ChinneryPF

SamuelsDC

2008 The distribution of mitochondrial DNA heteroplasmy due to random genetic drift. Am J Hum Genet 83 582 593

67. TillyJL

TillyKI

1995 Inhibitors of oxidative stress mimic the ability of follicle-stimulating hormone to suppress apoptosis in cultured rat ovarian follicles. Endocrinology 136 242 252

68. HusseinMR

2005 Apoptosis in the ovary: molecular mechanisms. Hum Reprod Update 11 162 177

69. TwigG

ElorzaA

MolinaAJ

MohamedH

WikstromJD

2008 Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27 433 446

70. TsukamotoS

KumaA

MurakamiM

KishiC

YamamotoA

2008 Autophagy is essential for preimplantation development of mouse embryos. Science 321 117 120

71. StewartJB

FreyerC

ElsonJL

LarssonNG

2008 Purifying selection of mtDNA and its implications for understanding evolution and mitochondrial disease. Nat Rev Genet 9 657 662

72. ZhouRR

WangB

WangJ

SchattenH

ZhangYZ

2010 Is the mitochondrial cloud the selection machinery for preferentially transmitting wild-type mtDNA between generations? Rewinding Muller's ratchet efficiently. Curr Genet 56 101 107

73. KlocM

BilinskiS

EtkinLD

2004 The Balbiani body and germ cell determinants: 150 years later. Curr Top Dev Biol 59 1 36

74. PeplingME

WilhelmJE

O'HaraAL

GephardtGW

SpradlingAC

2007 Mouse oocytes within germ cell cysts and primordial follicles contain a Balbiani body. Proc Natl Acad Sci U S A 104 187 192

75. KlocM

EtkinLD

1995 Two distinct pathways for the localization of RNAs at the vegetal cortex in Xenopus oocytes. Development 121 287 297

76. KlocM

EtkinLD

1998 Apparent continuity between the messenger transport organizer and late RNA localization pathways during oogenesis in Xenopus. Mech Dev 73 95 106

77. KlocM

LarabellC

EtkinLD

1996 Elaboration of the messenger transport organizer pathway for localization of RNA to the vegetal cortex of Xenopus oocytes. Dev Biol 180 119 130

78. ZhangYZ

OuyangYC

HouY

SchattenH

ChenDY

2008 Mitochondrial behavior during oogenesis in zebrafish: a confocal microscopy analysis. Dev Growth Differ 50 189 201

79. D'HerdeK

CallebautM

RoelsF

De PrestB

van NassauwL

1995 Homology between mitochondriogenesis in the avian and amphibian oocyte. Reprod Nutr Dev 35 305 311

80. CoxRT

SpradlingAC

2003 A Balbiani body and the fusome mediate mitochondrial inheritance during Drosophila oogenesis. Development 130 1579 1590

81. CoxRT

SpradlingAC

2006 Milton controls the early acquisition of mitochondria by Drosophila oocytes. Development 133 3371 3377

82. BrownDT

SamuelsDC

MichaelEM

TurnbullDM

ChinneryPF

2001 Random genetic drift determines the level of mutant mtDNA in human primary oocytes. Am J Hum Genet 68 533 536

83. MarchingtonD

MalikS

BanerjeeA

TurnerK

SamuelsD

2010 Information for genetic management of mtDNA disease: Sampling pathogenic mtDNA mutants in the human germline and in placenta. J Med Genet 47 257 261

84. DeanNL

BattersbyBJ

AoA

GosdenRG

TanSL

2003 Prospect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases. Mol Hum Reprod 9 631 638

85. GoossensV

De RyckeM

De VosA

StaessenC

MichielsA

2008 Diagnostic efficiency, embryonic development and clinical outcome after the biopsy of one or two blastomeres for preimplantation genetic diagnosis. Hum Reprod 23 481 492

86. BredenoordA

DondorpW

PenningsG

De Die-SmuldersC

SmeetsH

2009 Preimplantation genetic diagnosis for mitochondrial DNA disorders: ethical guidance for clinical practice. Eur J Hum Genet 17 1550 1559

87. ChinneryPF

ThorburnDR

SamuelsDC

WhiteSL

DahlHM

2000 The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both? Trends Genet 16 500 505

88. MarchingtonD

Scott-BrownM

BarlowD

JPoulton

2006 Moscaicism for mitochondrial DNA polymorphic variants in placenta has implications for the feasibility of prenatal diagnosis in mtDNA diseases. Eur J Hum Genet 14 816 823

89. CampbellKH

McWhirJ

RitchieWA

WilmutI

1996 Sheep cloned by nuclear transfer from a cultured cell line. Nature 380 64 66

90. SatoA

KonoT

NakadaK

IshikawaK

InoueS

2005 Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation. Proc Natl Acad Sci U S A 102 16765 16770

91. SillsES

TakeuchiT

TuckerMJ

PalermoGD

2004 Genetic and epigenetic modifications associated with human ooplasm donation and mitochondrial heteroplasmy - considerations for interpreting studies of heritability and reproductive outcome. Med Hypotheses 62 612 617

92. BarrittJA

BrennerCA

MalterHE

CohenJ

2001 Mitochondria in human offspring derived from ooplasmic transplantation. Hum Reprod 16 513 516

93. BrennerCA

KubischHM

PierceKE

2004 Role of the mitochondrial genome in assisted reproductive technologies and embryonic stem cell-based therapeutic cloning. Reprod Fertil Dev 16 743 751

94. ChiarattiMR

BressanFF

FerreiraCR

CaetanoAR

SmithLC

2010 Embryo mitochondrial DNA depletion is reversed during early embryogenesis in cattle. Biol Reprod 82 76 85

95. FerreiraCR

BurgstallerJP

PerecinF

GarciaJM

ChiarattiMR

2010 Pronounced segregation of donor mitochondria introduced by bovine ooplasmic transfer to the female germ-line. Biol Reprod 82 563 571

96. HuaS

ZhangY

LiXC

MaLB

CaoJW

2007 Effects of granulosa cell mitochondria transfer on the early development of bovine embryos in vitro. Cloning Stem Cells 9 237 246

97. El ShourbagySH

SpikingsEC

FreitasM

St JohnJC

2006 Mitochondria directly influence fertilisation outcome in the pig. Reproduction 131 233 245

98. PinkertCA

IrwinMH

JohnsonLW

MoffattRJ

1997 Mitochondria transfer into mouse ova by microinjection. Transgenic Res 6 379 383

99. McKenzieM

TrounceI

2000 Expression of Rattus norvegicus mtDNA in Mus musculus cells results in multiple respiratory chain defects. J Biol Chem 275 31514 31519

100. DeyR

BarrientosA

MoraesCT

2000 Functional constraints of nuclear-mitochondrial DNA interactions in xenomitochondrial rodent cell lines. J Biol Chem 275 31520 31527

101. NagaoY

TotsukaY

AtomiY

KanedaH

LindahlKF

1998 Decreased physical performance of congenic mice with mismatch between the nuclear and the mitochondrial genome. Genes Genet Syst 73 21 27

102. RoubertouxPL

SluyterF

CarlierM

MarcetB

Maarouf-VerayF

2003 Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice. Nat Genet 35 65 69

103. MeirellesF

SmithL

1998 Mitochondrial genotype segregation during preimplantation development in mouse heteroplasmic embryos. Genetics 148 877 883

104. BowlesE

CampbellK

JohnJS

2007 Nuclear transfer: preservation of a nuclear genome at the expense of its associated mtDNA genome(s).

JohnJS

CTDB Volume, The Mitochondrion in the Germline and Early Development San Diego, CA Elsevier

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