Skip to main content
SpringerLink
Log in

Differential effect of cataract-associated mutations in MAF on transactivation of MAF target genes

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Three mutations in the highly conserved DNA-binding region of c-MAF (R288P, K297R, and R299S) are associated with phenotypically distinct forms of autosomal dominant congenital cataract. However, the molecular mechanisms underlying this phenotypic diversity remain unclear. In this work, we have investigated the hypothesis that differential transactivation of MAF target genes could be one factor determining the phenotypic differences. Promoter constructs were generated for four human crystallin genes with conserved half-site MAF responsive elements (MARE). MAF expression constructs were constructed with the wildtype MAF sequence and with each of the three known mutations, i.e., R288P (associated with pulverulent cataract), K297R (associated with cerulean cataract), and R299S (associated with the most severe phenotype, congenital cataract, and microcornea syndrome). Transactivation was measured using luciferase reporter assays following cotransfection in HEK cells. Responsiveness to wildtype c-MAF was established for each of the four crystallin promoter constructs. The same constructs were then investigated using c-MAF mutants corresponding to each of the three mutations. A differential response was noted for each of the tested crystallin genes. The mutation R288P significantly reduced the expression of the CRYGA and CRYBA1 constructs but had no significant effect on the other two constructs. K297R did not lead to a significant reduction in expression of any of the four constructs, although there was a tendency toward reduced expression especially for the CRYGA construct. R299S, which is associated with the most severe phenotype, congenital cataract, and microcornea syndrome, was associated with the most severe overall effect on the transactivation of the four crystallin expression constructs. Our findings suggest that differential effects of mutations on the transactivation potential of c-MAF could be a molecular correlate of the striking genotype–phenotype correlations seen in cataract forms caused by mutations in the MAF gene.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ionides A, Francis P, Berry V, Mackay D, Bhattacharya S, Shiels A, Moore A (1999) Clinical and genetic heterogeneity in autosomal dominant cataract. Br J Ophthalmol 83:802–808

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Scott MH, Hejtmancik JF, Wozencraft LA, Reuter LM, Parks MM, Kaiser-Kupfer MI (1994) Autosomal dominant congenital cataract. Interocular phenotypic variability. Ophthalmology 101:866–871

    Article  PubMed  CAS  Google Scholar 

  3. Huang B, He W (2010) Molecular characteristics of inherited congenital cataracts. Eur J Med Genet 53:347–357

    Article  PubMed  Google Scholar 

  4. Vogt A (1922) Die Spezifität angeborener und erworbener Starformen für die einzelnen Linsenzonen. Graefes Arch Clin Exp Ophthalmol 108:219–228

    Article  Google Scholar 

  5. Armitage MM, Kivlin JD, Ferrell RE (1995) A progressive early onset cataract gene maps to human chromosome 17q24. Nat Genet 9:37–40

    Article  PubMed  CAS  Google Scholar 

  6. Litt M, Carrero-Valenzuela R, LaMorticella DM, Schultz DW, Mitchell TN, Kramer P, Maumenee IH (1997) Autosomal dominant cerulean cataract is associated with a chain termination mutation in the human beta-crystallin gene CRYBB2. Hum Mol Genet 6:665–668

    Article  PubMed  CAS  Google Scholar 

  7. Kramer P, Yount J, Mitchell T, LaMorticella D, Carrero-Valenzuela R, Lovrien E, Maumenee I, Litt M (1996) A second gene for cerulean cataracts maps to the beta crystallin region on chromosome 22. Genomics 35:539–542

    Article  PubMed  CAS  Google Scholar 

  8. Vanita Sarhadi V, Reis A, Jung M, Singh D, Sperling K, Singh JR, Burger J (2001) A unique form of autosomal dominant cataract explained by gene conversion between beta-crystallin B2 and its pseudogene. J Med Genet 38:392–396

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Nandrot E, Slingsby C, Basak A, Cherif-Chefchaouni M, Benazzouz B, Hajaji Y, Boutayeb S, Gribouval O, Arbogast L, Berraho A, Abitbol M, Hilal L (2003) Gamma-D crystallin gene (CRYGD) mutation causes autosomal dominant congenital cerulean cataracts. J Med Genet 40:262–267

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Vanita V, Singh D, Robinson PN, Sperling K, Singh JR (2006) A novel mutation in the DNA-binding domain of MAF at 16q23.1 associated with autosomal dominant “cerulean cataract” in an Indian family. Am J Med Genet A 140:558–566

    Article  PubMed  Google Scholar 

  11. Kataoka K, Nishizawa M, Kawai S (1993) Structure-function analysis of the maf oncogene product, a member of the b-Zip protein family. J Virol 67:2133–2141

    PubMed  CAS  PubMed Central  Google Scholar 

  12. Kataoka K, Noda M, Nishizawa M (1996) Transactivation activity of Maf nuclear oncoprotein is modulated by Jun, Fos and small Maf proteins. Oncogene 12:53–62

    PubMed  CAS  Google Scholar 

  13. Ogino H, Yasuda K (1998) Induction of lens differentiation by activation of a bZIP transcription factor, L-Maf. Science 280:115–118

    Article  PubMed  CAS  Google Scholar 

  14. Blank V, Andrews NC (1997) The Maf transcription factors: regulators of differentiation. Trends Biochem Sci 22:437–441

    Article  PubMed  CAS  Google Scholar 

  15. Reza HM, Urano A, Shimada N, Yasuda K (2007) Sequential and combinatorial roles of maf family genes define proper lens development. Mol Vis 13:18–30

    PubMed  CAS  PubMed Central  Google Scholar 

  16. Reza HM, Yasuda K (2004) Roles of Maf family proteins in lens development. Dev Dyn 229:440–448

    Article  PubMed  CAS  Google Scholar 

  17. Chesi M, Bergsagel PL, Shonukan OO, Martelli ML, Brents LA, Chen T, Schrock E, Ried T, Kuehl WM (1998) Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 91:4457–4463

    PubMed  CAS  Google Scholar 

  18. Berry V, Yang Z, Addison PK, Francis PJ, Ionides A, Karan G, Jiang L, Lin W, Hu J, Yang R, Moore A, Zhang K, Bhattacharya SS (2004) Recurrent 17 bp duplication in PITX3 is primarily associated with posterior polar cataract (CPP4). J Med Genet 41:e109

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Semina EV, Brownell I, Mintz-Hittner HA, Murray JC, Jamrich M (2001) Mutations on the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum Mol Genet 10:231–236

    Article  PubMed  CAS  Google Scholar 

  20. Merath K, Ronchetti A (2013) Sidjanin DJ (2013) Functional analysis of HSF4 mutations found in patients with autosomal recessive congenital cataracts. Invest Ophthalmol Vis Sci 54:6646–6654

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Azuma N, Hirakiyama A, Inoue T, Asaka A, Yamada M (2000) Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies. Hum Mol Genet 9:363–366

    Article  PubMed  CAS  Google Scholar 

  22. Nischal KK (2002) Corneal abnormalities. In: Wright KW, Spiegel PH (eds) Pediatric ophthalmology and strabismus, 2nd edn. Springer, New York, pp 391–429

    Google Scholar 

  23. Jamieson RV, Perveen R, Kerr B, Carette M, Yardley J, Heon E, Wirth MG, van Heyningen V, Donnai D, Munier F, Black GC (2002) Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma. Hum Mol Genet 11:33–42

    Article  PubMed  CAS  Google Scholar 

  24. Hansen L, Eiberg H, Rosenberg T (2007) Novel MAF mutation in a family with congenital cataract-microcornea syndrome. Mol Vis 13:2019–2022

    PubMed  CAS  Google Scholar 

  25. Hansen L, Mikkelsen A, Nürnberg P, Nürnberg G, Anjum I, Eiberg H, Rosenberg T (2009) Comprehensive mutational screening in a cohort of Danish families with hereditary congenital cataract. Invest Ophthalmol Vis Sci 50:3291–3303

    Article  PubMed  Google Scholar 

  26. Kataoka K, Noda M, Nishizawa M (1994) Maf nuclear oncoprotein recognizes sequences related to an AP-1 site and forms heterodimers with both Fos and Jun. Mol Cell Biol 14:700–712

    PubMed  CAS  PubMed Central  Google Scholar 

  27. Yamamoto T, Kyo M, Kamiya T, Tanaka T, Engel JD, Motohashi H, Yamamoto M (2006) Predictive base substitution rules that determine the binding and transcriptional specificity of Maf recognition elements. Genes Cells 11:575–591

    Article  PubMed  CAS  Google Scholar 

  28. Yoshida T, Ohkumo T, Ishibashi S, Yasuda K (2005) The 5′-AT-rich half-site of Maf recognition element: a functional target for bZIP transcription factor Maf. Nucleic Acids Res 33:3465–3478

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Xie Q, Cvekl A (2011) The orchestration of mammalian tissue morphogenesis through a series of coherent feed-forward loops. J Biol Chem 286:43259–43271

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Wolf LV, Yang Y, Wang J, Xie Q, Braunger B, Tamm ER, Zavadil J, Cvekl A (2009) Identification of pax6-dependent gene regulatory networks in the mouse lens. PLoS ONE 4:e4159

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ring BZ, Cordes SP, Overbeek PA, Barsh GS (2000) Regulation of mouse lens fiber cell development and differentiation by the Maf gene. Development 127:307–317

    PubMed  CAS  Google Scholar 

  32. Kawauchi S, Takahashi S, Nakajima O, Ogino H, Morita M, Nishizawa M, Yasuda K, Yamamoto M (1999) Regulation of lens fiber cell differentiation by transcription factor c-Maf. J Biol Chem 274:19254–19260

    Article  PubMed  CAS  Google Scholar 

  33. Kim JI, Li T, Ho IC, Grusby MJ, Glimcher LH (1999) Requirement for the c-Maf transcription factor in crystallin gene regulation and lens development. Proc Natl Acad Sci USA 96:3781–3785

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Perveen R, Favor J, Jamieson RV, Ray DW, Black GC (2007) A heterozygous c-Maf transactivation domain mutation causes congenital cataract and enhances target gene activation. Hum Mol Genet 16:1030–1038

    Article  PubMed  CAS  Google Scholar 

  35. Cvekl A, Piatigorsky J (1996) Lens development and crystallin gene expression: many roles for Pax-6. BioEssays 18:621–630

    Article  PubMed  CAS  Google Scholar 

  36. Yang Y, Cvekl A (2005) Tissue-specific regulation of the mouse alphaA-crystallin gene in lens via recruitment of Pax6 and c-Maf to its promoter. J Mol Biol 351:453–469

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Yang Y, Stopka T, Golestaneh N, Wang Y, Wu K, Li A, Chauhan BK, Gao CY, Cveklová K, Duncan MK, Pestell RG, Chepelinsky AB, Skoultchi AI, Cvekl A (2006) Regulation of alphaA-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin. EMBO J 25:2107–2118

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Liu FY, Tang XC, Deng M, Chen P, Ji W, Zhang X, Gong L, Woodward Z, Liu J, Zhang L, Sun S, Liu JP, Wu K, Wu MX, Liu XL, Yu MB, Liu Y, Li DW (2012) The tumor suppressor p53 regulates c-Maf and Prox-1 to control lens differentiation. Curr Mol Med 12:917–928

    Article  PubMed  Google Scholar 

  39. Nishiguchi S, Wood H, Kondoh H, Lovell-Badge R, Episkopou V (1998) Sox1 directly regulates the gamma-crystallin genes and is essential for lens development in mice. Genes Dev 12:776–781

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Cvekl A, Mitton KP (2010) Epigenetic regulatory mechanisms in vertebrate eye development and disease. Heredity 105:135–151

    Article  PubMed  CAS  Google Scholar 

  41. Litt M, Kramer P, LaMorticella DM, Murphey W, Lovrien EW, Weleber RG (1998) Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA. Hum Mol Genet 7:471–474

    Article  PubMed  CAS  Google Scholar 

  42. Graw J, Klopp N, Illig T, Preising MN, Lorenz B (2006) Congenital cataract and macular hypoplasia in humans associated with a de novo mutation in CRYAA and compound heterozygous mutations in P. Graefes Arch Clin Exp Ophthalmol 244:912–919

    Article  PubMed  CAS  Google Scholar 

  43. Mackay DS, Andley UP, Shiels A (2003) Cell death triggered by a novel mutation in the alphaA-crystallin gene underlies autosomal dominant cataract linked to chromosome 21q. Eur J Hum Genet 11:784–793

    Article  PubMed  CAS  Google Scholar 

  44. Khan AO, Aldahmesh MA, Meyer B (2007) Recessive congenital total cataract with microcornea and heterozygote carrier signs caused by a novel missense CRYAA mutation (R54C). Am J Ophthalmol 144:949–952

    Article  PubMed  CAS  Google Scholar 

  45. Beby F, Commeaux C, Bozon M, Denis P, Edery P, Morle L (2007) New phenotype associated with an Arg116Cys mutation in the CRYAA gene: nuclear cataract, iris coloboma, and microphthalmia. Arch Ophthalmol 125:213–216

    Article  PubMed  CAS  Google Scholar 

  46. Santana A, Waiswol M, Arcieri ES, Cabral de Vasconcellos JP, Barbosa de Melo M (2009) Mutation analysis of CRYAA, CRYGC, and CRYGD associated with autosomal dominant congenital cataract in Brazilian families. Mol Vis 15:793–800

    PubMed  CAS  PubMed Central  Google Scholar 

  47. Bateman JB, Geyer DD, Flodman P, Johannes M, Sikela J, Walter N, Moreira AT, Clancy K, Spence MA (2000) A new betaA1-crystallin splice junction mutation in autosomal dominant cataract. Invest Ophthalmol Vis Sci 41:3278–3285

    PubMed  CAS  Google Scholar 

  48. Padma T, Ayyagari R, Murty JS, Basti S, Fletcher T, Rao GN, Kaiser-Kupfer M, Hejtmancik JF (1995) Autosomal dominant zonular cataract with sutural opacities localized to chromosome 17q11-12. Am J Hum Genet 57:840–845

    PubMed  CAS  PubMed Central  Google Scholar 

  49. Qi Y, Jia H, Huang S, Lin H, Gu J, Su H, Zhang T, Gao Y, Qu L, Li D, Li Y (2004) A deletion mutation in the betaA1/A3 crystallin gene (CRYBA1/A3) is associated with autosomal dominant congenital nuclear cataract in a Chinese family. Hum Genet 114:192–197

    Article  PubMed  CAS  Google Scholar 

  50. Reddy MA, Bateman OA, Chakarova C, Ferris J, Berry V, Lomas E, Sarra R, Smith MA, Moore AT, Bhattacharya SS, Slingsby C (2004) Characterization of the G91del CRYBA1/3-crystallin protein: a cause of human inherited cataract. Hum Mol Genet 13:945–953

    Article  PubMed  CAS  Google Scholar 

  51. Klopp N, Favor J, Loster J, Lutz RB, Neuhauser-Klaus A, Prescott A, Pretsch W, Quinlan RA, Sandilands A, Vrensen GF, Graw J (1998) Three murine cataract mutants (Cat2) are defective in different gamma-crystallin genes. Genomics 52:152–158

    Article  PubMed  CAS  Google Scholar 

  52. Billingsley G, Santhiya ST, Paterson AD, Ogata K, Wodak S, Hosseini SM, Manisastry SM, Vijayalakshmi P, Gopinath PM, Graw J, Heon E (2006) CRYBA4, a novel human cataract gene, is also involved in microphthalmia. Am J Hum Genet 79:702–709

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Castorino JJ, Gallagher-Colombo SM, Levin AV, Fitzgerald PG, Polishook J, Kloeckener-Gruissem B, Ostertag E, Philp NJ (2011) Juvenile cataract-associated mutation of solute carrier SLC16A12 impairs trafficking of the protein to the plasma membrane. Invest Ophthalmol Vis Sci 52:6774–6784

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. Hough TA, Bogani D, Cheeseman MT, Favor J, Nesbit MA, Thakker RV, Lyon MF (2004) Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification. Proc Natl Acad Sci USA 101:13566–13571

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. Hu S, Wang B, Qi Y, Lin H (2012) The Arg233Lys AQP0 mutation disturbs aquaporino-calmodulin interaction causing polymorphic congenital cataract. PLoS ONE 7:e37637

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Park JE, Son AI, Hua R, Wang L, Zhang X, Zhou R (2012) Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. PLoS ONE 7:e36564

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by Grant sanctioned to VV from the Department of Biotechnology, Government of India (Grant number BT/IN/German/13/VK/2010), and the BundesministeriumfürBildung und Forschung (BMBF, project number IND 10/036) to PNR under the framework of Indo-German bilateral cooperation for research.

Author information

Authors and Affiliations

  1. Department of Human Genetics, Guru Nanak Dev University, Amritsar, 143005, Punjab, India

    Vanita Vanita

  2. Institut Für Medizinische Genetik Und Humangenetik, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Gao Guo, Claus-Eric Ott & Peter N. Robinson

  3. Dr. Daljit Singh Eye Hospital, Sheranwala Gate, Amritsar, India

    Daljit Singh

  4. Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin, Berlin, Germany

    Peter N. Robinson

  5. Max-Planck-Institut für Molekulare Genetik, Berlin, Germany

    Peter N. Robinson

Authors
  1. Vanita Vanita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gao Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daljit Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claus-Eric Ott
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter N. Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Vanita Vanita or Peter N. Robinson.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vanita, V., Guo, G., Singh, D. et al. Differential effect of cataract-associated mutations in MAF on transactivation of MAF target genes. Mol Cell Biochem 396, 137–145 (2014). https://doi.org/10.1007/s11010-014-2150-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-014-2150-z

Keywords

Search

Navigation