Identification of three novel plasminogen (PLG) gene mutations in a series of 23 patients with low PLG activity

Jürgen Klammt; Louise Kobelt; Dilek Aktas; Ismet Durak; Aslan Gokbuget; Quintin Hughes; Murat Irkec; Idil Kurtulus; Elisabetta Lapi; Hadas Mechoulam; Roberto Mendoza-Londono; Joseph S. Palumbo; Hansjörg Steitzer; Khalid F. Tabbara; Zeynep Ozbek; Neri Pucci; Talia Sotomayor; Marian Sturm; Tim Drogies; Maike Ziegler; Volker Schuster

doi:10.1160/TH10-04-0216

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 105(03): 454-460
DOI: 10.1160/TH10-04-0216

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Identification of three novel plasminogen (PLG) gene mutations in a series of 23 patients with low PLG activity

Authors

Jürgen Klammt

¹Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
Louise Kobelt

¹Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
Dilek Aktas

²Hacettepe University Medical School, Department of Genetics, Ankara, Turkey
Ismet Durak

³Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey
Aslan Gokbuget

⁴Istanbul University, Faculty of Dentistry, Dept. of Periodontology, Capa, Istanbul
Quintin Hughes

⁵School of Surgery and Pathology, University of Western Australia, Perth, Australia
Murat Irkec

⁶Department of Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey
Idil Kurtulus

⁴Istanbul University, Faculty of Dentistry, Dept. of Periodontology, Capa, Istanbul
Elisabetta Lapi

⁷Children’s Hospital “Anna Meyer”, Florence, Italy
Hadas Mechoulam

⁸Department of Ophthalmology, Hadassah Medical Center, Jerusalem, Israel
Roberto Mendoza-Londono

⁹Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Canada
Joseph S. Palumbo

¹⁰Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA
Hansjörg Steitzer

¹¹Austrian Red Cross, Transfusion Service for Upper Austria, Linz, Austria
Khalid F. Tabbara

¹²The Eye Center and The Eye Foundation for Research in Ophthalmology, Riyadh, Saudi Arabia
Zeynep Ozbek

³Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey
Neri Pucci

⁷Children’s Hospital “Anna Meyer”, Florence, Italy
Talia Sotomayor

¹³Pediatric Pulmonary Medicine, WVU Children‘s Hospital; Morgantown, USA
Marian Sturm

¹⁴Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia
Tim Drogies

¹⁵Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany
Maike Ziegler

¹Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
Volker Schuster

¹Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany

Abstract

Summary

Inherited severe hypoplasminogenaemia is a multisystemic disorder leading to deficient extravascular fibrinolysis. As a clinical consequence wound healing capacity of mucous membranes is markedly impaired leading to ligneous conjunctivitis and several other manifestations. Here we report the molecular genetic and clinical findings on 23 new cases with severe hypoplasminogenaemia. Homozygous or compound-heterozygous mutations in the plasminogen (PLG) gene were found in 16 of 23 patients (70%), three of which were novel mutations reported here for the first time (C166Y, Y264S, IVS10–7T/G). Compared to 79 previously published cases, clinical manifestations of the current group of patients showed higher percentages of ligneous periodontitis, congenital hydrocephalus, and involvement of the female genital tract. In contrast, involvement of the gastrointestinal or urogenital tract was not observed in any of the cases. Patients originated to a large extent (61%) from Turkey and the Middle East, and showed a comparably frequent occurrence of consanguinity of affected families and a greater female to male ratio than was derived from previous reports in the literature. Individual treatment of ligneous conjunctivitis included topical plasminogen or heparin eye drops, topical or systemic fresh frozen plasma, and surgical removal of ligneous pseudomembranes, mostly with modest or transient efficacy. In conclusion, the present study underscores the broad range of clinical manifestations in PLG-deficient patients with a trend to regional differences. Transmission of genetic and clinical data to the recently established Plasminogen Deficiency Registry should help to determine the prevalence of the disease and to develop more efficient treatment strategies.

Keywords

Inherited hypoplasminogenaemia - clinical heterogeneity - PLG gene mutations

Full Text

References

References
1 Schuster V, Hugle B, Tefs K. Plasminogen deficiency. J Thromb Haemost 2007; 5: 2315-2322.
2 Caputo R, Pucci N, Mori F. et al. Long-term efficacy of surgical removal of pseudomembranes in a child with ligneous conjunctivitis treated with plasminogen eyedrops. Thromb Haemost 2008; 100: 1196-1198.
3 Tefs K, Gueorguieva M, Klammt J. et al. Molecular and clinical spectrum of type I plasminogen deficiency: A series of 50 patients. Blood 2006; 108: 3021-3026.
4 Petersen TE, Martzen MR, Ichinose A. et al. Characterization of the gene for human plasminogen, a key proenzyme in the fibrinolytic system. J Biol Chem 1990; 265: 6104-6111.
5 Forsgren M, Raden B, Israelsson M. et al. Molecular cloning and characterization of a full-length cDNA clone for human plasminogen. FEBS Lett 1987; 213: 254-260.
6 Tuncbilek E, Ozguc M. Application of medical genetics in Turkey. Turk J Pediatr 2007; 49: 353-359.
7 Al Gazali L, Hamamy H, Al Arrayad S. Genetic disorders in the Arab world. Br Med J 2006; 333: 831-834.
8 Eash D, Waggoner D, Chung J. et al. Calibration of 6q subtelomere deletions to define genotype/phenotype correlations. Clin Genet 2005; 67: 396-403.
9 Chi AC, Prichard E, Richardson MS. et al. Pseudomembranous disease (ligneous inflammation) of the female genital tract, peritoneum, gingiva, and paranasal sinuses associated with plasminogen deficiency. Ann Diagn Pathol 2009; 13: 132-139.
10 Biswas J, Billingham K, Biswas S. et al. Ligneous cervicitis: an unusual cause of post-coital bleeding in a postmenopausal woman. J Obstet Gynaecol 2009; 29: 163-165.
11 Lotan TL, Tefs K, Schuster V. et al. Inherited plasminogen deficiency presenting as ligneous vaginitis: a case report with molecular correlation and review of the literature. Hum Pathol 2007; 38: 1569-1575.
12 Suzuki T, Ikewaki J, Iwata H. et al. The first two Japanese cases of severe type I congenital plasminogen deficiency with ligneous conjunctivitis: Successful treatment with direct thrombin inhibitor and fresh plasma. Am J Hematol 2009; 84: 363-365.
13 Schott D, Dempfle CE, Beck P. et al. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. N Engl J Med 1998; 339: 1679-1686.
14 Lejeune F, Maquat LE. Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr Opin Cell Biol 2005; 17: 309-315.
15 van der Meulen MA, van der Meulen MJ, te Meerman GJ. Recurrence risk for germinal mosaics revisited. J Med Genet 1995; 32: 102-104.
16 Marti D, Schaller J, Ochensberger B. et al. Expression, purification and characterization of the recombinant kringle 2 and kringle 3 domains of human plasminogen and analysis of their binding affinity for omega-aminocarboxylic acids. Eur J Biochem 1994; 219: 455-462.
17 Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009; 4: 1073-1081.
18 Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res 2002; 30: 3894-3900.
19 Schuster V, Mingers AM, Seidenspinner S. et al. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood 1997; 90: 958-966.
20 Gurlu VP, Demir M, Alimgil ML. et al. Systemic and topical fresh-frozen plasma treatment in a newborn with ligneous conjunctivitis. Cornea 2008; 27: 501-503.
21 Heidemann DG, Williams GA, Hartzer M. et al. Treatment of ligneous conjunctivitis with topical plasmin and topical plasminogen. Cornea 2003; 22: 760-762.
22 Tabbara KF. Prevention of ligneous conjunctivitis by topical and subconjunctival fresh frozen plasma. Am J Ophthalmol 2004; 138: 299-300.
23 Watts P, Suresh P, Mezer E. et al. Effective treatment of ligneous conjunctivitis with topical plasminogen. Am J Ophthalmol 2002; 133: 451-455.
24 Kurtulus I, Gokbuget A, Efeoglu A. et al. Hypoplasminogenemia with ligneous periodontitis: a failed local therapeutic approach. J Periodontol 2007; 78: 1164-1175.
25 Toker H, Toker MI, Goze F. et al. A ligneous periodontitis and conjunctival lesions in a patient with plasminogen deficiency. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 103: e35-e38.
26 Fine G, Bauer K, Al Mohaya M. et al. Successful treatment of ligneous gingivitis with warfarin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009; 107: 77-80.
27 Kraft J, Lieb W, Zeitler P. et al. Ligneous conjunctivitis in a girl with severe type I plasminogen deficiency. Graefes Arch Clin Exp Ophthalmol 2000; 238: 797-800.
28 McCullough K, Nguyen H, Stechschulte D. et al. Ligneous conjunctivitis: a case re-port with multiorgan involvement. Histopathology 2007; 50: 511-513.
29 Rodriguez-Ares MT, Abdulkader I, Blanco A. et al. Ligneous conjunctivitis: a clinicopathological, immunohistochemical, and genetic study including the treatment of two sisters with multiorgan involvement. Virchows Arch 2007; 451: 815-821.
30 Sartori MT, Saggiorato G, Pellati D. et al. Contraceptive pills induce an improvement in congenital hypoplasminogenemia in two unrelated patients with ligneous conjunctivitis. Thromb Haemost 2003; 90: 86-91.
31 Schuster V, Seidenspinner S, Zeitler P. et al. Compound-heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis. Blood 1999; 93: 3457-3466.
32 Schuster V, Zeitler P, Seregard S. et al. Homozygous and compound-heterozygous type I plasminogen deficiency is a common cause of ligneous conjunctivitis. Thromb Haemost 2001; 85: 1004-1010.
33 Siboni SM, Spreafico M, Menegatti M. et al. Molecular characterization of an Italian patient with plasminogen deficiency and ligneous conjunctivitis. Blood Coagul Fibrinolysis 2007; 18: 81-84.
34 Yohe SL, Reyes M, Johnson DA. et al. Plasminogen deficiency as a rare cause of conjunctivitis and lymphadenopathy. Am J Surg Pathol 2009; 33: 313-319.