Congenital macrothrombocytopenia associated with a combination of functional polymorphisms in the TUBB1 gene

Summary

Congenital thrombocytopenia in childhood and adolescence requires an extensive diagnostic workup to find the underlying reason. We report on a 13-year-old female patient who was incidentally found to have moderate thrombocytopenia which was also diagnosed in her father and brother. Within the microscopic evaluation of a peripheral blood smear macrothrombocytes were found. Immunofluorescence microscopy of the patient’s platelets detected the lack of D1-tubulin. Analysis of the TUBB1 gene revealed three known missense variants in heterozygous state which in combination might explain the D1-tubulin defect.

Zusammenfassung

Eine angeborene Thrombozytopenie im Kindes-und Jugendalter erfordert eine umfangreiche diagnostische Aufarbeitung, um die zugrundeliegende Ursache zu finden. Wir berichten von einer 13 Jahre alten Patientin, bei welcher der Zufallsbefund einer moderaten Thrombozytopenie erhoben wurde, die auch bei ihrem Vater und Bruder diagnostiziert werden konnte. Bei der mikroskopischen Beurteilung eines peripheren Blutausstrichs imponierten Makrothrombozyten. Mittels Immunfluoreszenzmikroskopie der Thrombozyten konnte keinerlei D1-Tubulin detektiert werden. Die Analyse des TUBB1-Gens führte zum Nachweis von drei vorbeschriebenen heterozygoten Missense-Varianten, welche in ihrer Kombination den D1-Tubulin-Defekt erklären könnten.

Keywords

Congenital thrombocytopenia - macrothrombocytes - β1-tubulin defect

Schlüsselwörter

Angeborene Thrombozytopenie - Makrothrombozyten - β1-Tubulin-Defekt

• References

• 1 Balduini CL, Savoia A. Genetics of familial forms of thrombocytopenia. Hum Genet 2012; 131: 1821-1832.
• 2 Basciano PA, Bussel J, Hafeez Z. et al. The beta 1 tubulin R307H single nucleotide polymorphism is associated with treatment failures in immune thrombocytopenia (ITP). Br J Haematol 2013; 160: 237-243.
• 3 Basciano PA, Matakas J, Pecci A. et al. ß-1 tubulin R307H SNP alters microtubule dynamics and affects severity of a hereditary thrombocytopenia. J Thromb Haemost 2015; 13: 651-965.
• 4 Freson K, De Vos R, Wittevrongel C. et al. The TUBB1 Q43P functional polymorphism reduces the risk of cardiovascular disease in men by modulating platelet function and structure. Blood 2005; 106: 2356-2362.
• 5 Italiano Jr JE, Bergmeier W, Tiwari S. et al. Mechanisms and implications of platelet discoid shape. Blood 2003; 101: 4789-4796.
• 6 Knöfler R, Eberl W, Schulze H. et al. Diagnose angeborener Störungen der Thrombozytenfunktion. Hämostaseologie 2014; 34: 201-212.
• 7 Kunishima S, Kobayashi R, Itoh TJ. et al. Mutation of the beta1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly. Blood 2009; 113: 458-461.
• 8 Kunishima S, Nishimura S, Suzuki H. et al. TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia. Eur J Haematol 2014; 92: 276-282.
• 9 Leandro-García LJ, Leskelä S, Inglada-Pérez L. et al. Hematologic β-tubulin VI isoform exhibits genetic variability that influences paclitaxel toxicity. Cancer Res 2012; 72: 4744-4752.
• 10 Lecine P, Italiano Jr JE, Kim SW. et al. Hematopoietic-specific beta 1 tubulin participates in a pathway of platelet biogenesis dependent on the transcription factor NF-E2. Blood 2000; 96: 1366-1373.
• 11 Navarro-Núñez L, Lozano ML, Rivera J. et al. The association of the beta1-tubulin Q43P polymorphism with intracerebral hemorrhage in men. Haematologica 2007; 92: 513-518.
• 12 Navarro-Núñez L, Teruel R, Antón AI. et al. Rare homozygous status of P43 β1-tubulin polymorphism causes alterations in platelet ultrastructure. Thromb Haemost 2011; 105: 855-863.
• 13 Schwer HD, Lecine P, Tiwari S. et al. A lineage-restricted and divergent beta-tubulin isoform is essential for the biogenesis, structure and function of blood platelets. Curr Biol 2001; 11: 579-586.
• 14 Streif W, Knöfler R, Eberl W. et al. Therapy of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e.V.). Hämostaseologie 2014; 34: 269-275.
• 15 Tauer JT, Gneuss A, Lohse JE. et al. Evaluation of desmopressin effect on primary haemostasis in pediatric patients with aspirin-like defect as hereditary thrombocytopathy. Klin Pädiatr 2011; 223: 169-172.