Skip to main content
SpringerLink
Log in

Identification of recurrent c.742G>T nonsense mutation in ECM1 in Pakistani families suffering from lipoid proteinosis

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Lipoid proteinosis (LP) is one of the rare, recessive autosomal disorders clinically characterized by widespread deposition of hyaline-like material in the skin, mucosa and viscera. Classical features include beaded eyelid papules, laryngeal infiltration and hoarseness of voice caused by pathogenic mutations in the ECM1gene located on 1q21.2. In present study ethnically different, three consanguineous Pakistani families with typical cutaneous features of LP were analysed to investigate the underlying molecular basis. PCR based linkage analysis using microsatellite markers localized the families to locus 1q21.2, harboring ECM1 gene. To identify the mutation in the candidate gene (ECM1), Sanger sequencing was carried out. All the families were found to carry c.742 G>T nonsense mutation in exon 7 of the ECM1 gene that resulted in a truncated ECM1 protein containing 247 amino acids instead of 540 (p.E248X). To further investigate the impact and importance of mutation in LP pathogenesis we applied different bioinformatics tools. In silico studies has predicted lack of functional domains and 65 % shorter ECM1 mutant protein. It is the first report of recurrence mutation from Pakistan as c.742G>T nonsense mutation was found in three ethnically different Pakistani families with LP. Study strengthens the conclusion that c.742G>T mutation is the pathological cause of LP. Furthermore, data also support the fact that exon 7 is one of the most common hot spots of pathological mutations in ECM1. The absence of functional domains and truncated sequence most likely contribute to the lack of ECM1 function and thereby influence several aspects of dermal homeostasis that leads to LP pathogenesis.

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
Fig. 5

Similar content being viewed by others

References

  1. Urbach E, Wiethe C (1929) Lipoidosis cutis et mucosae. Virchows Arch 273:285–319

    Article  Google Scholar 

  2. Hamada T, McLean WH, Ramsay M, Ashton GH, Nanda A, Jenkins T, Edelstein I, South AP, Bleck O, Wessagowit V, Mallipeddi R, Orchard GE, Wan H, Dopping-Hepenstal PJ, Mellerio JE, Whittock NV, Munro CS, van Steensel MA, Steijlen PM, Ni J, Zhang L, Hashimoto T, Eady RA, McGrath JA (2002) Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1). Hum Mol Genet 11(7):833–840

    Article  PubMed  CAS  Google Scholar 

  3. Van Hougenhouck-Tulleken W, Chan I, Hamada T, Thornton H, Jenkins T, McLean WH, McGrath JA, Ramsay M (2004) Clinical and molecular characterization of lipoid proteinosis in Namaqualand, South Africa. Br J Dermatol 151(2):413–423. doi:10.1111/j.1365-2133.2004.06076.x

    Article  PubMed  CAS  Google Scholar 

  4. Chan I, Liu L, Hamada T, Sethuraman G, McGrath JA (2007) The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1. Exp Dermatol 16(11):881–890. doi:10.1111/j.1600-0625.2007.00608.x

    Article  PubMed  CAS  Google Scholar 

  5. Hamada T (2002) Lipoid proteinosis. Clin Exp Dermatol 27(8):624–629

    Article  PubMed  CAS  Google Scholar 

  6. Hofer PA (1973) Urbach–Wiethe disease (lipoglycoproteinosis; lipoid proteinosis; hyalinosis cutis et mucosae).A review. Acta Derm Venereol Suppl (Stockh) 53:1–52

    CAS  Google Scholar 

  7. Chan I, El-Zurghany A, Zendah B, Benghazil M, Oyama N, Hamada T, McGrath JA (2003) Molecular basis of lipoid proteinosis in a Libyan family. Clin Exp Dermatol 28(5):545–548

    Article  PubMed  CAS  Google Scholar 

  8. Liu W, Xu W, Yang X, Lian S (2012) A novel missense mutation of the ECM1 gene in a Chinese patient with lipoid proteinosis. Clin Exp Dermatol 37(1):28–30. doi:10.1111/j.1365-2230.2011.04153.x

    Article  PubMed  CAS  Google Scholar 

  9. Sander CS, Sercu S, Ziemer M, Hipler UC, Elsner P, Thiele JJ, Merregaert J (2006) Expression of extracellular matrix protein 1 (ECM1) in human skin is decreased by age and increased upon ultraviolet exposure. Br J Dermatol 154(2):218–224. doi:10.1111/j.1365-2133.2005.07001.x

    Article  PubMed  CAS  Google Scholar 

  10. Sercu S, Oyama N, Merregaert J (2009) Importance of extracellular matrix protein 1 (ECM1) in maintaining the functional integrity of the human skin. Open Dermatol J 3:44–51. doi:10.2174/1874372200903010044

    Article  CAS  Google Scholar 

  11. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, vol 2. Cold Spring Harbor Laboratory, New York

    Google Scholar 

  12. Nasir M, Latif A, Ajmal M, Qamar R, Naeem M, Hameed A (2011) Molecular analysis of lipoid proteinosis: identification of a novel nonsense mutation in the ECM1 gene in a Pakistani family. Diagn Pathol 6:69. doi:10.1186/1746-1596-6-69

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Rost B, Sander C (1994) Combining evolutionary information and neural networks to predict protein secondary structure. Proteins 19(1):55–72. doi:10.1002/prot.340190108

    Article  PubMed  CAS  Google Scholar 

  14. Lupas A (1996) Prediction and analysis of coiled-coil structures. Method Enzymol 266:513–525

    Article  CAS  Google Scholar 

  15. Linding R, Russell RB, Neduva V, Gibson TJ (2003) GlobPlot: exploring protein sequences for globularity and disorder. Nucleic Acids Res 31(13):3701–3708

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Ferre F, Clote P (2005) DiANNA: a web server for disulfide connectivity prediction. Nucleic Acids Res 33 (Web Server issue):W230–232. doi:10.1093/nar/gki412

  17. Zdobnov EM, Apweiler R (2001) InterProScan—an integration platform for the signature-recognition methods in InterPro. Bioinformatics 17(9):847–848

    Article  PubMed  CAS  Google Scholar 

  18. Zhang Y (2008) I-TASSER server for protein 3D structure prediction. BMC Bioinform 9:40. doi:10.1186/1471-2105-9-40

    Article  CAS  Google Scholar 

  19. Lovell SC, Davis IW, Arendall WB 3rd, de Bakker PI, Word JM, Prisant MG, Richardson JS, Richardson DC (2003) Structure validation by Calpha geometry: phi, psi and Cbeta deviation. Proteins 50(3):437–450. doi:10.1002/prot.10286

    Article  PubMed  CAS  Google Scholar 

  20. Notredame C, Higgins DG, Heringa J (2000) T-Coffee: a novel method for fast and accurate multiple sequence alignment. J Mol Biol 302(1):205–217. doi:10.1006/jmbi.2000.4042

    Article  PubMed  CAS  Google Scholar 

  21. Holm L, Sander C (1993) Protein structure comparison by alignment of distance matrices. J Mol Biol 233(1):123–138. doi:10.1006/jmbi.1993.1489

    Article  PubMed  CAS  Google Scholar 

  22. Horton P, Park KJ, Obayashi T, Fujita N, Harada H, Adams-Collier CJ, Nakai K (2007) WoLF PSORT: protein localization predictor. Nucleic Acids Res 35 (Web Server issue):W585–587. doi:10.1093/nar/gkm259

  23. Petersen TN, Brunak S, von Heijne G, Nielsen H (2011) SignalP 4.0: discriminating signal peptides from transmembrane regions. Nat Method 8(10):785–786. doi:10.1038/nmeth.1701

    Article  CAS  Google Scholar 

  24. Chan I, Sethuraman G, Sharma VK, Bruning E, Hamada T, McGrath JA (2004) Molecular basis of lipoid proteinosis in two Indian siblings. J Dermatol 31(9):764–766

    PubMed  CAS  Google Scholar 

  25. Sercu S, Zhang M, Oyama N, Hansen U, Ghalbzouri AE, Jun G, Geentjens K, Zhang L, Merregaert JH (2008) Interaction of extracellular matrix protein 1 with extracellular matrix components: ECM1 is a basement membrane protein of the skin. J Invest Dermatol 128(6):1397–1408. doi:10.1038/sj.jid.5701231

    Article  PubMed  CAS  Google Scholar 

  26. Maquat LE (2005) Nonsense-mediated mRNA decay in mammals. J Cell Sci 118(Pt 9):1773–1776. doi:10.1242/jcs.01701

    Article  PubMed  CAS  Google Scholar 

  27. Mongiat M, Fu J, Oldershaw R, Greenhalgh R, Gown AM, Iozzo RV (2003) Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis. J Biol Chem 278(19):17491–17499. doi:10.1074/jbc.M210529200

    Article  PubMed  CAS  Google Scholar 

  28. Smits P, Ni J, Feng P, Wauters J, Van Hul W, Boutaibi ME, Dillon PJ, Merregaert J (1997) The human extracellular matrix gene 1 (ECM1): genomic structure, cDNA cloning, expression pattern, and chromosomal localization. Genomics 45(3):487–495. doi:10.1006/geno.1997.4918

    Article  PubMed  CAS  Google Scholar 

  29. Bhalerao J, Tylzanowski P, Filie JD, Kozak CA, Merregaert J (1995) Molecular cloning, characterization, and genetic mapping of the cDNA coding for a novel secretory protein of mouse. Demonstration of alternative splicing in skin and cartilage. J Biol Chem 270(27):16385–16394

    Article  PubMed  CAS  Google Scholar 

  30. Sercu S, Zhang L, Merregaert J (2008) The extracellular matrix protein 1: its molecular interaction and implication in tumor progression. Cancer Invest 26(4):375–384. doi:10.1080/07357900701788148

    Article  PubMed  CAS  Google Scholar 

  31. Kong L, Tian Q, Guo F, Mucignat MT, Perris R, Sercu S, Merregaert J, Di Cesare PE, Liu CJ (2010) Interaction between cartilage oligomeric matrix protein and extracellular matrix protein 1 mediates endochondral bone growth. Matrix Biol 29(4):276–286. doi:10.1016/j.matbio.2010.01.007

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  32. Fujimoto N, Terlizzi J, Brittingham R, Fertala A, McGrath JA, Uitto J (2005) Extracellular matrix protein 1 interacts with the domain III of fibulin-1C and 1D variants through its central tandem repeat 2. Biochem Biophys Res Commun 333(4):1327–1333. doi:10.1016/j.bbrc.2005.06.046

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank the patients and their family members who contributed in this study. We are also grateful to Mr. Syed Husnain Haider for technical assistance.

Conflict of interest

The author(s) declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Institute of Biomedical & Genetic Engineering, 24-Mauve Area, G-9/1, Islamabad, Pakistan

    Muhammad Nasir, Nafees Ahmad & Abdul Hameed

  2. Dr. Simeen’s Aesthetic Skin & Laser Clinic, Rawalpindi, Pakistan

    Simeen Ber Rahman

  3. Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich-German Research Center for Environmental Health, Neuherberg, Germany

    Christian M. K. Sieber

  4. International Islamic University, Islamabad, Pakistan

    Asif Mir

  5. Latif Clinics, Rawalpindi, Pakistan

    Amir Latif

  6. Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan

    Salman Akbar Malik

Authors
  1. Muhammad Nasir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simeen Ber Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christian M. K. Sieber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Asif Mir
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amir Latif
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nafees Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Salman Akbar Malik
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Abdul Hameed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Muhammad Nasir.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 38 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nasir, M., Rahman, S.B., Sieber, C.M.K. et al. Identification of recurrent c.742G>T nonsense mutation in ECM1 in Pakistani families suffering from lipoid proteinosis. Mol Biol Rep 41, 2085–2092 (2014). https://doi.org/10.1007/s11033-014-3057-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-014-3057-1

Keywords

Search

Navigation