Skip to main content

Advertisement

SpringerLink
Log in

Expression Analysis of MLH3, MLH1, and MSH4 in Maturation Arrest

  • Original Articles
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The expression of DNA mismatch repair (DMMR) genes in patients with maturation arrest (MA) was analyzed. Samples were subjected to mutL homolog 3 (MLH3) mutation analysis by denaturing high-performance liquid chromatography/sequencing and quantification of MMR expression in testicular tissue by real-time polymerase chain reaction (PCR). Microsatellite instability assays were negative. Two missense and 1 intronic mutations were found. The missense mutation 2531C/T (P844 L), predicted to affect MLH3 function, was found in 3 MA cases in association with the intronic variant IVS9 + 66G/A. Relative messenger RNA (mRNA) quantification identified 2 patients who overexpressed MLH3, 1 of them also overexpressing mutL homolog 1 (MLH1). The latter also presented the 2531C/T-IVS9 + 66G/A mutation. In conclusion, we suggest that a predominance of MLH3 expression might favor the MLH1/MLH3 complex which then would compete with the MLH1/PMS2 complexes. This could convey disruption of the relative stoichiometry between MLH1/MLH3 and MLH1/PMS2 complexes, thus causing meiosis failure, as MLH1/PMS2 complexes are supposed to replace MLH1/MLH3 during diplonema.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Vogt PH, Edelmann A, Kirsch S, et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet. 1996;5(7):933–943.

    Article  PubMed  CAS  Google Scholar 

  2. Sá R, Neves R, Fernandes S, et al. Cytological and expression studies and quantitative analysis of the temporal and stage specific effects of follicle stimulating hormone and testosterone during cocultures of the normal human seminiferous epithelium. Biol Reprod. 2008;79(5):962–975.

    Article  PubMed  CAS  Google Scholar 

  3. Sousa M, Cremades N, Silva J, et al. Predictive value of testicular histology in secretory azoospermic subgroups and clinical outcome after microinjection of fresh and frozen-thawed sperm and spermatids. Hum Reprod. 2002;17(7):1800–1810.

    Article  PubMed  CAS  Google Scholar 

  4. Sá R, Sousa M, Cremades N, Silva J, Barros A. Spermatid injection: current status. In: Rizk B, Garcia-Velasco JA, Sallam HN, Makrigiannakis A, eds. Textbook of Infertility and Assisted Reproduction (MSRM: Mediterranean Society for Reproductive Medicine). London: Cambridge University Press; Chapter 53, 2008:491–503.

    Google Scholar 

  5. Habermann B, Mi H-F, Edelmann A, et al. DAZ (Deleted in AZoospermia) genes encode proteins located in human late spermatids and in sperm tails. Hum Reprod. 1998;13(2):363–369.

    Article  PubMed  CAS  Google Scholar 

  6. Fernandes S, Huellen K, Gonc¸alves J, et al. High frequency of DAZ1/DAZ2 gene deletions in patients with severe oligozoospermia. Mol Hum Reprod. 2002;8(3):286–298.

    Article  PubMed  CAS  Google Scholar 

  7. Ferrás C, Fernandes S, Marques CJ, et al. AZF and DAZ gene copy specific deletion analysis in maturation arrest and Sertoli cell only syndrome. Mol Hum Reprod. 2004;10(10):755–761.

    Article  PubMed  CAS  Google Scholar 

  8. Calogero AE, Garofalo MR, Barone N, et al. Spontaneous regression over time of the germinal epithelium in a Y chromosome-microdeleted patient. Hum Reprod. 2001;16(9):1845–1848.

    Article  PubMed  CAS  Google Scholar 

  9. Lipkin SM, Wang V, Stoler DL, et al. Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: evidence for somatic mutation in colorectal cancers. Hum Mut. 2001; 17(5):389–396.

    Article  PubMed  CAS  Google Scholar 

  10. Kane MF, Loda M, Gaida GM, et al. Methylation of the hMLH1 promoter correlates with lack of expression of in sporadic colon tumors and mismatch repair-defective human tumor cels. Cancer Res. 1997;57(5):808–811.

    PubMed  CAS  Google Scholar 

  11. Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of Hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med. 1998;338(21):1481–1487.

    Article  PubMed  CAS  Google Scholar 

  12. Cannavo E, Marra G, Sabates-Bellver J, et al. Expression of the Mutl homologue hMLH3 in human cells and its role in DNA mismatch repair. Cancer Res. 2005;65(23):10759–10766.

    Article  PubMed  CAS  Google Scholar 

  13. Lipkin SM, Wang V, Jacoby R, et al. MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Nat Genet. 2000;24(1):27–35.

    Article  PubMed  CAS  Google Scholar 

  14. Loukola A, Vikki S, Singh J, Launonen V, Aaltonen LA. Germline and somatic mutation analysis of MLH3 in MSI-positive colorectal cancer. Am J Pathol. 2000;157(2):347–352.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Akiyama Y, Nagasaki H, Nakajima T, Sakai H, Nomizu T, Yuasa Y. Infrequent frameshift mutations in the simple repeat sequences of hMLH3 in hereditary nonpolyposis colorectal cancers. Jpn J Clin Oncol. 2001;31(2):61–64.

    Article  PubMed  CAS  Google Scholar 

  16. Wu Y, Berends MJ, Sijmons RH, et al. A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nat Genet. 2001;29(2): 137–138.

    Article  PubMed  CAS  Google Scholar 

  17. Hienonem T, Laiho P, Salovaara R, et al. Little evidence for involvement of MLH3 in colorectal cancer predisposition. Int J Cancer. 2003;106(2):292–296.

    Article  CAS  Google Scholar 

  18. Liu HX, Zhou XL, Liu T, et al. The role of hMLH3 in familial colorectal cancer. Cancer Res, 2003;63(8):1894–1899.

    CAS  Google Scholar 

  19. Muramatsu M, Kinoshita K, Fagarasan S, et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000;102(5):553–563.

    Article  PubMed  CAS  Google Scholar 

  20. Revy P, Muto T, Levy Y, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2). Cell. 2000;102(5):565–575.

    Article  PubMed  CAS  Google Scholar 

  21. Li Z, Scherer SJ, Ronai D, et al. Examination of Msh6- and Msh3-deficient mice in class switching reveals overlapping and distinct roles of Muts homologues in antibody diversification. J Exp Med. 2004;200(1):47–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Li Z, Peled JU, Zhao C, et al. A role for Mlh3 in somatic hyper-mutation. DNA Repair. 2006;5(6):675–682.

    Article  PubMed  CAS  Google Scholar 

  23. Kondo E, Horii A, Fukushige S. The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2. Nucleic Acids Res. 2001;29(8):1695–1702.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Chen PC, Dudley S, Hahen W, et al. Contributions be Mutl homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Cancer Res. 2005;65(19):8662–8670.

    Article  PubMed  CAS  Google Scholar 

  25. Lipkin SM, Moens PB, Wang V, et al. Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat Genet. 2002;31(4): 385–390.

    Article  PubMed  CAS  Google Scholar 

  26. Santucci-Darmanin S, Neyton S, Lespinasse F, Saunieres A, Gaudray P, Paquis-Flucklinger V. The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination. Hum Mol Genet. 2002;11(15):1697–1706.

    Article  PubMed  CAS  Google Scholar 

  27. Marcon E, Moens P. MLH1p and MLH3p localize to precociously induced chiasmata of okadaic-acid-treated mouse spermatocytes. Genetics. 2003;165(4):2283–2287.

    PubMed  PubMed Central  CAS  Google Scholar 

  28. Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58(22):5248–5257.

    PubMed  CAS  Google Scholar 

  29. Ferrás C, Zhou XL, Sousa M, Lindblom A, Barros A. DNA mismatch repair gene hMLH3 variants in meiotic arrest. Fertil Steril. 2007;88(6):1681–1684.

    Article  PubMed  CAS  Google Scholar 

  30. Sousa M, Cremades N, Alves C, et al. Developmental potential of human spermatogenic cells co-cultered with Sertoli cells. Hum Reprod. 2002;17(1):161–172.

    Article  PubMed  Google Scholar 

  31. Taylor NP, Powell MA, Gibb RK, et al. MLH3 mutation in endometrial cancer. Cancer Res. 2006;66(15):7502–7508.

    Article  PubMed  CAS  Google Scholar 

  32. Baker SM, Bronner CE, Zhang L, et al. Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. Cell. 1995;82(2):309–319.

    Article  PubMed  CAS  Google Scholar 

  33. Edelmann W, Cohen PE, Kane M, et al. Meiotic pachytene arrest in MLH1-deficient mice. Cell. 1996;85(7):1125–1134.

    Article  PubMed  CAS  Google Scholar 

  34. Edelmann W, Cohen PE, Kneitz B, et al. Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat Genet. 1999;21(1):123–127.

    Article  PubMed  CAS  Google Scholar 

  35. Kneitz B, Cohen PE, Avdievich E, et al. MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Genes Dev. 2000;14(9):1085–1097.

    PubMed  PubMed Central  CAS  Google Scholar 

  36. Nudell D, Castillo M, Turek PJ, Pera RR. Increased frequency of mutations in DNA from infertile men with meiotic arrest. Hum Reprod. 2000;15(6):1289–1294.

    Article  PubMed  CAS  Google Scholar 

  37. Terribas E, Bonache S, Garcia-Arevalo M, et al. Changes in the expression profile of the meiosis-involved mismatch repair genes in impaired human spermatogenesis. J Androl. 2010;31(4):346–357.

    Article  PubMed  CAS  Google Scholar 

  38. Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res. 2001;11(5):863–874.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Chromosome Instability and Dynamics, Institute for Molecular Cell Biology (IBMC), Rua do Campo Alegre, Porto, Portugal

    Cristina Ferrás PhD

  2. Department of Genetics, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto, Portugal

    Susana Fernandes PhD & Alberto Barros MD, PhD

  3. Centre for Reproductive Genetics Alberto Barros, Frente, Porto, Portugal

    Joaquina Silva MD & Alberto Barros MD, PhD

  4. Department of Microscopy, Laboratory of Cell Biology, Biomedical Research Multidisciplinary Unit (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Lg Prof Abel Salazar Porto, 24099-003, Porto, Portugal

    Mário Sousa MD, PhD

Authors
  1. Cristina Ferrás PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susana Fernandes PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joaquina Silva MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alberto Barros MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mário Sousa MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mário Sousa MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ferrás, C., Fernandes, S., Silva, J. et al. Expression Analysis of MLH3, MLH1, and MSH4 in Maturation Arrest. Reprod. Sci. 19, 587–596 (2012). https://doi.org/10.1177/1933719111428521

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719111428521

Keywords

Search

Navigation