Genetics of mitochondrial dysfunction and infertility

Clinical Genetics

Volumn 91, Issue 2, 2017, Pages 199-207

  Demain, L A M ^a,b   Conway, G S ^c   Newman, W G ^a,b  

^a ST MARY S HOSPITAL   (United Kingdom)

^b UNIVERSITY OF MANCHESTER   (United Kingdom)

^c UNIVERSITY COLLEGE LONDON HOSPITALS   (United Kingdom)

Author keywords

infertility; mitochondria; POLG; primary ovarian insufficiency

Indexed keywords

MITOCHONDRIAL DNA; MITOCHONDRIAL PROTEIN; DNA DIRECTED DNA POLYMERASE; POLG PROTEIN, HUMAN;

DISEASE ASSOCIATION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; FEMALE INFERTILITY; GENE; GENETIC VARIABILITY; GENITAL SYSTEM; HUMAN; MALE INFERTILITY; MITOCHONDRIAL DNA DEPLETION SYNDROME; MITOCHONDRIAL GENETICS; MITOCHONDRION; NONHUMAN; POLG GENE; POPULATION GENETICS; PRIORITY JOURNAL; REVIEW; FEMALE; GENETICS; INFERTILITY THERAPY; MALE; METABOLISM; OOCYTE; PATHOLOGY; SPERMATOZOON;

DNA-DIRECTED DNA POLYMERASE; FEMALE; HUMANS; INFERTILITY, FEMALE; INFERTILITY, MALE; MALE; MITOCHONDRIA; OOCYTES; REPRODUCTIVE TECHNIQUES, ASSISTED; SPERMATOZOA;

EID: 85006504109     PISSN: 00099163     EISSN: 13990004     Source Type: Journal    
DOI: 10.1111/cge.12896     Document Type: Review

References (90)

1. Reeve AK, Lightowlers RN. An introduction to mitochondria. In: Reeve KA, Krishnan JK, Duchen RM, et al., eds. Mitochondrial dysfunction in neurodegenerative disorders. London: Springer London, 2012: 3–18.
2. Chinnery PF. Mitochondrial disorders overview. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). University of Washington, Seattle, WA, 1993.
3. Zorrilla M, Yatsenko AN. The genetics of infertility: current status of the field. Curr Genet Med Rep 2013: 1.
4. Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update 2005: 11: 391–410.
5. St John JC, Jokhi RP, Barratt CL. The impact of mitochondrial genetics on male infertility. Int J Androl 2005: 28: 65–73.
6. Santos TA, El Shourbagy S, St John JC. Mitochondrial content reflects oocyte variability and fertilization outcome. Fertil Steril 2006: 85: 584–591.
7. Sousa AP, Amaral A, Baptista M et al. Not all sperm are equal: functional mitochondria characterize a subpopulation of human sperm with better fertilization potential. PLoS One 2011: 6: e18112.
8. Jansen RP. Germline passage of mitochondria: quantitative considerations and possible embryological sequelae. Hum Reprod 2000: 15 (Suppl. 2): 112–128.
9. Van Blerkom J. Mitochondrial function in the human oocyte and embryo and their role in developmental competence. Mitochondrion 2011: 11: 797–813.
10. Jansen RP, Burton GJ. Mitochondrial dysfunction in reproduction. Mitochondrion 2004: 4: 577–600.
11. Ramalho-Santos J, Amaral S. Mitochondria and mammalian reproduction. Mol Cell Endocrinol 2013: 379: 74–84.
12. Perez GI, Jurisicova A, Wise L et al. Absence of the proapoptotic Bax protein extends fertility and alleviates age-related health complications in female mice. Proc Natl Acad Sci USA 2007: 104: 5229–5234.
13. Amaral A, Lourenco B, Marques M et al. Mitochondria functionality and sperm quality. Reproduction 2013: 146: R163–R174.
14. Amaral A, Ramalho-Santos J, St John JC. The expression of polymerase gamma and mitochondrial transcription factor A and the regulation of mitochondrial DNA content in mature human sperm. Hum Reprod 2007: 22: 1585–1596.
15. Ruiz-Pesini E, Diez C, Lapena AC et al. Correlation of sperm motility with mitochondrial enzymatic activities. Clin Chem 1998: 44: 1616–1620.
16. Brower JV, Rodic N, Seki T et al. Evolutionarily conserved mammalian adenine nucleotide translocase 4 is essential for spermatogenesis. J Biol Chem 2007: 282: 29658–29666.
17. Brower JV, Lim CH, Jorgensen M et al. Adenine nucleotide translocase 4 deficiency leads to early meiotic arrest of murine male germ cells. Reproduction 2009: 138: 463–470.
18. Lim CH, Brower JV, Resnick JL et al. Adenine nucleotide translocase 4 is expressed within embryonic ovaries and dispensable during oogenesis. Reprod Sci 2015: 22: 250–257.
19. Lu B, Poirier C, Gaspar T et al. A mutation in the inner mitochondrial membrane peptidase 2-like gene (Immp2l) affects mitochondrial function and impairs fertility in mice. Biol Reprod 2008: 78: 601–610.
20. George SK, Jiao Y, Bishop CE et al. Oxidative stress is involved in age-dependent spermatogenic damage of Immp2l mutant mice. Free Radic Biol Med 2012: 52: 2223–2233.
21. Gispert S, Parganlija D, Klinkenberg M et al. Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors. Hum Mol Genet 2013: 22: 4871–4887.
22. Newman WG, Friedman TB, Conway GS. Perrault Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). University of Washington, Seattle, WA, 1993.
23. Demain LAM, Urquhart JE, O'Sullivan J et al. Expanding the genotypic spectrum of Perrault syndrome. Clin Genet 2016. DOI: 10.1111/cge.12776.
24. Nakada K, Sato A, Yoshida K et al. Mitochondria-related male infertility. Proc Natl Acad Sci USA 2006: 103: 15148–15153.
25. Trifunovic A, Wredenberg A, Falkenberg M et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 2004: 429: 417–423.
26. Luoma P, Melberg A, Rinne JO et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 2004: 364: 875–882.
27. Pandya A. Nonsyndromic hearing loss and deafness, mitochondrial. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). University of Washington, Seattle, WA, 1993.
28. Barrientos A, Casademont J, Genis D et al. Sporadic heteroplasmic single 5.5 kb mitochondrial DNA deletion associated with cerebellar ataxia, hypogonadotropic hypogonadism, choroidal dystrophy, and mitochondrial respiratory chain complex I deficiency. Hum Mutat 1997: 10: 212–216.
29. Harvey JN, Barnett D. Endocrine dysfunction in Kearns-Sayre syndrome. Clin Endocrinol (Oxf) 1992: 37: 97–103.
30. El-Hattab AW, Adesina AM, Jones J et al. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab 2015: 116: 4–12.
31. Ishii A, Watanabe S, Ohkoshi N et al. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) associated with hypothalamo-pituitary hypofunction – a case report. Rinsho Shinkeigaku 1991: 31: 179–183.
32. Ohkoshi N, Ishii A, Shiraiwa N et al. Dysfunction of the hypothalamic-pituitary system in mitochondrial encephalomyopathies. J Med 1998: 29: 13–29.
33. Joko T, Iwashige K, Hashimoto T et al. A case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes associated with diabetes mellitus and hypothalamo-pituitary dysfunction. Endocr J 1997: 44: 805–809.
34. Topaloglu H, Seyrantepe V, Kandemir N et al. mtDNA nt3243 mutation, external ophthalmoplegia, and hypogonadism in an adolescent girl. Pediatr Neurol 1998: 18: 429–431.
35. Robeck S, Stefan H, Engelhardt A et al. Follow-up studies and disorders of endocrinologic function in MELAS syndrome. Nervenarzt 1996: 67: 465–470.
36. Spiropoulos J, Turnbull DM, Chinnery PF. Can mitochondrial DNA mutations cause sperm dysfunction? Mol Hum Reprod 2002: 8: 719–721.
37. Melone MA, Tessa A, Petrini S et al. Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERFF phenotype. Arch Neurol 2004: 61: 269–272.
38. Mancuso M, Orsucci D, Angelini C et al. The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender? J Neurol 2014: 261: 504–510.
39. Martikainen MH, Kytovuori L, Majamaa K. Juvenile Parkinsonism, hypogonadism and Leigh-like MRI changes in a patient with m.4296G>A mutation in mitochondrial DNA. Mitochondrion 2013: 13: 83–86.
40. Kytovuori L, Lipponen J, Rusanen H et al. A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism. J Neurol 2016: 263 (11): 2188–2195.
41. Schaefer AM, McFarland R, Blakely EL et al. Prevalence of mitochondrial DNA disease in adults. Ann Neurol 2008: 63: 35–39.
42. Thorburn DR, Rahman S. Mitochondrial DNA-associated Leigh syndrome and NARP. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). University of Washington, Seattle, WA, 1993.
43. Pagnamenta AT, Taanman JW, Wilson CJ et al. Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum Reprod 2006: 21: 2467–2473.
44. Bekheirnia MR, Zhang W, Eble T et al. POLG mutation in a patient with cataracts, early-onset distal muscle weakness and atrophy, ovarian dysgenesis and 3-methylglutaconic aciduria. Gene 2012: 499: 209–212.
45. Pitceathly RD, Smith C, Fratter C et al. Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics. Brain 2012: 135: 3392–3403.
46. Takata A, Kato M, Nakamura M et al. Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia. Genome Biol 2011: 12: R92.
47. Spelbrink JN, Li FY, Tiranti V et al. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 2001: 28: 223–231.
48. Nikali K, Suomalainen A, Saharinen J et al. Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Hum Mol Genet 2005: 14: 2981–2990.
49. Lonnqvist T, Paetau A, Valanne L et al. Recessive twinkle mutations cause severe epileptic encephalopathy. Brain 2009: 132: 1553–1562.
50. Morino H, Pierce SB, Matsuda Y et al. Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features. Neurology 2014: 83: 2054–2061.
51. Fratter C, Gorman GS, Stewart JD et al. The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO. Neurology 2010: 74: 1619–1626.
52. Spinazzola A, Viscomi C, Fernandez-Vizarra E et al. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet 2006: 38: 570–575.
53. Mendelsohn BA, Mehta N, Hameed B et al. Adult-onset fatal neurohepatopathy in a woman caused by MPV17 mutation. JIMD Rep 2014: 13: 37–41.
54. Carod-Artal FJ, Herrero MD, Lara MC et al. Cognitive dysfunction and hypogonadotrophic hypogonadism in a Brazilian patient with mitochondrial neurogastrointestinal encephalomyopathy and a novel ECGF1 mutation. Eur J Neurol 2007: 14: 581–585.
55. Garone C, Tadesse S, Hirano M. Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain 2011: 134: 3326–3332.
56. Kalkan IH, Tayfur O, Oztas E et al. A novel finding in MNGIE (mitochondrial neurogastrointestinal encephalomyopathy): hypergonadotropic hypogonadism. Hormones 2012: 11: 377–379.
57. Pallister PD, Opitz JM. The Perrault syndrome: autosomal recessive ovarian dysgenesis with facultative, non-sex-limited sensorineural deafness. Am J Med Genet 1979: 4: 239–246.
58. Gottschalk ME, Coker SB, Fox LA. Neurologic anomalies of Perrault syndrome. Am J Med Genet 1996: 65: 274–276.
59. Jenkinson EM, Clayton-Smith J, Mehta S et al. Perrault syndrome: further evidence for genetic heterogeneity. J Neurol 2012: 259: 974–976.
60. Pierce SB, Walsh T, Chisholm KM et al. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault syndrome. Am J Hum Genet 2010: 87: 282–288.
61. Pierce SB, Chisholm KM, Lynch ED et al. Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci USA 2011: 108: 6543–6548.
62. Pierce SB, Gersak K, Michaelson-Cohen R et al. Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. Am J Hum Genet 2013: 92: 614–620.
63. Jenkinson EM, Rehman AU, Walsh T et al. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet 2013: 92: 605–613.
64. de Launoit Y, Adamski J. Unique multifunctional HSD17B4 gene product: 17 beta-hydroxysteroid dehydrogenase 4 and D-3-hydroxyacyl-coenzyme A dehydrogenase hydratase involved in Zellweger syndrome. J Mol Endocrinol 1999: 22: 227–240.
65. Diodato D, Ghezzi D, Tiranti V. The mitochondrial aminoacyl tRNA synthetases: genes and syndromes. Int J Cell Biol 2014: 2014: 787956.
66. Kang SG, Dimitrova MN, Ortega J et al. Human mitochondrial ClpP is a stable heptamer that assembles into a tetradecamer in the presence of ClpX. J Biol Chem 2005: 280: 35424–35432.
67. Bonnefond L, Fender A, Rudinger-Thirion J et al. Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS. Biochemistry 2005: 44: 4805–4816.
68. Dallabona C, Diodato D, Kevelam S et al. Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology 2014: 82: 2063–2071.
69. Tong ZB, Sullivan SD, Lawless LM et al. Five mutations of mitochondrial DNA polymerase-gamma (POLG) are not a prevalent etiology for spontaneous 46,XX primary ovarian insufficiency. Fertil Steril 2010: 94: 2932–2934.
70. Duncan AJ, Knight JA, Costello H et al. POLG mutations and age at menopause. Hum Reprod 2012: 27: 2243–2244.
71. Bonomi M, Somigliana E, Cacciatore C et al. Blood cell mitochondrial DNA content and premature ovarian aging. PLoS One 2012: 7: e42423.
72. Perry JR, Corre T, Esko T et al. A genome-wide association study of early menopause and the combined impact of identified variants. Hum Mol Genet 2013: 22: 1465–1472.
73. Stolk L, Perry JR, Chasman DI et al. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nat Genet 2012: 44: 260–268.
74. Rovio AT, Marchington DR, Donat S et al. Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat Genet 2001: 29: 261–262.
75. Jensen M, Leffers H, Petersen JH et al. Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. Hum Reprod 2004: 19: 65–70.
76. Krausz C, Guarducci E, Becherini L et al. The clinical significance of the POLG gene polymorphism in male infertility. J Clin Endocrinol Metab 2004: 89: 4292–4297.
77. Aknin-Seifer IE, Touraine RL, Lejeune H et al. Is the CAG repeat of mitochondrial DNA polymerase gamma (POLG) associated with male infertility? A multi-centre French study. Hum Reprod 2005: 20: 736–740.
78. Harris TP, Gomas KP, Weir F et al. Molecular analysis of polymerase gamma gene and mitochondrial polymorphism in fertile and subfertile men. Int J Androl 2006: 29: 421–433.
79. Kumar M, Pathak D, Kriplani A et al. Nucleotide variations in mitochondrial DNA and supra-physiological ROS levels in cytogenetically normal cases of premature ovarian insufficiency. Arch Gynecol Obstet 2010: 282: 695–705.
80. Venkatesh S, Kumar M, Sharma A et al. Oxidative stress and ATPase6 mutation is associated with primary ovarian insufficiency. Arch Gynecol Obstet 2010: 282: 313–318.
81. Zhen X, Wu B, Wang J et al. Increased incidence of mitochondrial cytochrome C oxidase 1 gene mutations in patients with primary ovarian insufficiency. PLoS One 2015: 10: e0132610.
82. Baklouti-Gargouri S, Ghorbel M, Ben Mahmoud A et al. Mitochondrial DNA mutations and polymorphisms in asthenospermic infertile men. Mol Biol Rep 2013: 40: 4705–4712.
83. Kao S, Chao HT, Wei YH. Mitochondrial deoxyribonucleic acid 4977-bp deletion is associated with diminished fertility and motility of human sperm. Biol Reprod 1995: 52: 729–736.
84. Bahrehmand Namaghi I, Vaziri H. Sperm mitochondrial DNA deletion in Iranian infertiles with asthenozoospermia. Andrologia 2016. DOI: 10.1111/and.12627.
85. St John JC, Jokhi RP, Barratt CL. Men with oligoasthenoteratozoospermia harbour higher numbers of multiple mitochondrial DNA deletions in their spermatozoa, but individual deletions are not indicative of overall aetiology. Mol Hum Reprod 2001: 7: 103–111.
86. Ieremiadou F, Rodakis GC. Correlation of the 4977 bp mitochondrial DNA deletion with human sperm dysfunction. BMC Res Notes 2009: 2: 18.
87. Kao SH, Chao HT, Wei YH. Multiple deletions of mitochondrial DNA are associated with the decline of motility and fertility of human spermatozoa. Mol Hum Reprod 1998: 4: 657–666.
88. May-Panloup P, Chretien MF, Jacques C et al. Low oocyte mitochondrial DNA content in ovarian insufficiency. Hum Reprod 2005: 20: 593–597.
89. Schaefer AM, Walker M, Turnbull DM et al. Endocrine disorders in mitochondrial disease. Mol Cell Endocrinol 2013: 379: 2–11.
90. Cummins JM, Jequier AM, Martin R, Mehmet D, Goldblatt J. Semen levels of mitochondrial DNA deletions in men attending an infertility clinic do not correlate with phenotype. Int J Androl 1998: 21: 47–52.