Thrombosis and Haemostasis, Inhaltsverzeichnis Thromb Haemost 2012; 108(04): 654-661DOI: 10.1160/TH12-02-0088 Blood Coagulation, Fibrinolysis and Cellular Haemostasis Schattauer GmbH Maternal chromosome 4 heterodisomy/isodisomy and Bβ chain Trp323X mutation resulting in severe hypodysfibrinogenaemia Authors Institutsangaben Qiulan Ding 1 Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China Qi Ouyang 2 State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai, China 3 Department of Laboratory Medicine, Eye & ENT Hospital affiliated to Fudan University, Shanghai, China Xiaodong Xi 2 State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai, China Xuefeng Wang 1 Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China Yiping Shen 4 Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China 5 Department of Laboratory Medicine, Children's Hospital, Boston , Massachusetts, USA Hongli Wang 2 State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai, China Artikel empfehlen Abstract Artikel einzeln kaufen(opens in new window) Summary We report a rare case of congenital hypodysfibrinogenaemia due to maternal uniparental disomy of chromosome 4 (mat UPD 4) and a maternally inherited novel nonsense mutation Trp323X in the fibrinogen Bβ chain (FGB) gene. Western blot analysis of patient's plasma revealed an abnormal fibrinogen which consisted of truncated Bβ chain and normal Aα and γ chains. Patient's clinical history and laboratory evidence are presented. Microsatellite genotyping analysis revealed a mixed nature of heterodisomy and isodisomy along chromosome 4. High density SNP genotyping array analysis further confirmed the mat UPD 4 and defined two segments of chromosome 4 (4pter-p15.33 and 4q31.21–4q32.3) as maternal isodisomy (iUPD4) and the remaining regions as maternal heterodisomy (hUPD4), with the FGB gene carrying the mutation resided in the iUPD4 region on the long (q) arm. It was predicted that the segmental nature of iUPD and hUPD was caused by three recombination events at positions around 167.96 cM, 145.51 cM and 14.40 cM on chromosome 4 followed by a meiosis I non-disjunction. This case is clinically and molecularly unique and offers an opportunity for understanding novel mechanisms of congenital hypodysfibrinogenaemia associated with complex UPD and fibrinogen secretion. Keywords KeywordsFibrinogen / fibrin - haemostasis - gene mutations - thrombosis Volltext Referenzen References 1 Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 03: 1894-1904. 2 Matsuda M, Sugo T. Hereditary disorders of fibrinogen. Ann NY Acad Sci 2001; 936: 65-88. 3 Koopman J, Haverkate F, Grimbergen J. et al. Fibrinogen Marburg: a homozygous case of dysfibrinogenemia, lacking amino acids A alpha 461–610 (Lys 461 AAA-->stop TAA). Blood 1992; 80: 1972-1979. 4 Lefebvre P, Velasco PT, Dear A. et al. Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AalphaIVS4 + 1G>T mutation and an AalphaGln328 truncation (fibrinogen Keokuk). Blood 2004; 103: 2571-2576. 5 Hayes T. Dysfibrinogenemia and thrombosis. Arch Pathol Lab Med 2002; 126: 1387-1390. 6 Vu D, Bolton-Maggs PH, Parr JR. et al. Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion. Blood 2003; 102: 4413-4415. 7 Vu D, Di Sanza C, Caille D. et al. Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia. Hum Mol Genet 2005; 14: 3271-3280. 8 Vu D, Neerman-Arbez M. Molecular mechanisms accounting for fibrinogen deficiency: from large deletions to intracellular retention of misfolded proteins. J Thromb Haemost 2007; 05 (Suppl. 01) 125-131. 9 Robinson WP. Mechanisms leading to uniparental disomy and their clinical consequences. Bioessays 2000; 22: 452-459. 10 Faas BH, van der Burgt I, Kooper AJ. et al. Identification of clinically significant, submicroscopic chromosome alterations and UPD in fetuses with ultrasound anomalies using genome-wide 250k SNP array analysis. J Med Genet 2010; 47: 586-594. 11 Spena S, Duga S, Asselta R. et al. Congenital afibrinogenaemia caused by uniparental isodisomy of chromosome 4 containing a novel 15-kb deletion involving fibrinogen Aalpha-chain gene. Eur J Hum Genet 2004; 12: 891-898. 12 Collier DA, Barrett TG, Curtis D. et al. Linkage of Wolfram syndrome to chromosome 4p16.1 and evidence for heterogeneity. Am J Hum Genet 1996; 59: 855-863. 13 Cottrell C, Mendell J, Hart-Kothari M. et al. Maternal uniparental disomy of chromosome 4 in a patient with limb-girdle muscular dystrophy 2E confirmed by SNP array technology. Clin Genet 2012; 81: 578-583. 14 Middleton FA, Trauzzi MG, Shrimpton AE. et al. Complete maternal uniparental isodisomy of chromosome 4 in a subject with major depressive disorder detected by high density SNP genotyping arrays. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 28-32. 15 Tompson SW, Ruiz-Perez VL, Wright MJ. et al. Ellis-van Creveld syndrome resulting from segmental uniparental disomy of chromosome 4. J Med Genet 2001; 38: E18. 16 Yang XP, Inazu A, Yagi K. et al. Abetalipoproteinemia caused by maternal isodisomy of chromosome 4q containing an intron 9 splice acceptor mutation in the microsomal triglyceride transfer protein gene. Arterioscler Thromb Vasc Biol 1999; 19: 1950-1955. 17 Neerman-Arbez M, Vu D, Abu-Libdeh B. et al. Prenatal diagnosis for congenital afibrinogenemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family. Blood 2003; 101: 3492-3494. 18 Zhang JZ, Redman CM. Identification of B beta chain domains involved in human fibrinogen assembly. J Biol Chem 1992; 267: 21727-21732. 19 Homer VM, Mullin JL, Brennan SO. et al. Novel Aalpha chain truncation (fibrinogen Perth) resulting in low expression and impaired fibrinogen polymerization. J Thromb Haemost 2003; 01: 1245-1250. 20 Ridgway HJ, Brennan SO, Faed JM. et al. Fibrinogen Otago: a major alpha chain truncation associated with severe hypofibrinogenaemia and recurrent miscarriage. Br J Haematol 1997; 98: 632-639.
