Genetics of Familial Forms of Thrombocytopenia

Overview

Journal Hum Genet

Specialty Genetics

Date 2012 Aug 14

PMID 22886561

Citations 23

Authors

Carlo L Balduini

Anna Savoia

Affiliations

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Abstract

The joint application of clinical and genetic investigation to patients with inherited thrombocytopenias, as well as the availability of new methods for studying megakaryopoiesis, has greatly expanded the knowledge of these disorders in the last few years with regard to their etiology, pathogenesis and clinical aspects. In particular, new diseases have been described, as deriving from mutations in the genes FLNA, TUBB1, ITGA2/ITGB3, ANKRD26, CYCS, and ABCG5 or ABCG8. Moreover, forms previously considered separate entities were found to be different clinical aspects of a single disease. For instance, identification of MYH9 as the gene whose mutations cause the May-Hegglin anomaly led to the recognition that Sebastian platelet syndrome, Epstein syndrome, and Fechtner syndrome derive from mutations of the same gene and describe overlapping disorders. Despite these advances, knowledge of hereditary thrombocytopenias is still far from satisfactory because for approximately half of the patients it is not possible to formulate a definite diagnosis in that their illnesses has not yet been described. In this review, we provide a systematic description of hereditary thrombocytopenias as we know them today, giving special attention to genetic aspects.

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References

Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E . MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore). 2003; 82(3):203-15. DOI: 10.1097/01.md.0000076006.64510.5c. View

Rees D, Iolascon A, Carella M, OMarcaigh A, Kendra J, Jowitt S . Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol. 2005; 130(2):297-309. DOI: 10.1111/j.1365-2141.2005.05599.x. View

Nurden A, Nurden P . The gray platelet syndrome: clinical spectrum of the disease. Blood Rev. 2006; 21(1):21-36. DOI: 10.1016/j.blre.2005.12.003. View

Balduini C, Pecci A, Savoia A . Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias. Br J Haematol. 2011; 154(2):161-74. DOI: 10.1111/j.1365-2141.2011.08716.x. View

Ciovacco W, Raskind W, Kacena M . Human phenotypes associated with GATA-1 mutations. Gene. 2008; 427(1-2):1-6. PMC: 2601579. DOI: 10.1016/j.gene.2008.09.018. View

Ghevaert C, Salsmann A, Watkins N, Schaffner-Reckinger E, Rankin A, Garner S . A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the alphaIIbbeta3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia. Blood. 2007; 111(7):3407-14. DOI: 10.1182/blood-2007-09-112615. View

Balduini A, Pallotta I, Malara A, Lova P, Pecci A, Viarengo G . Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes. J Thromb Haemost. 2008; 6(11):1900-7. DOI: 10.1111/j.1538-7836.2008.03132.x. View

Pecci A, Biino G, Fierro T, Bozzi V, Mezzasoma A, Noris P . Alteration of liver enzymes is a feature of the MYH9-related disease syndrome. PLoS One. 2012; 7(4):e35986. PMC: 3338476. DOI: 10.1371/journal.pone.0035986. View

Larson M, Watson S . Regulation of proplatelet formation and platelet release by integrin alpha IIb beta3. Blood. 2006; 108(5):1509-14. DOI: 10.1182/blood-2005-11-011957. View

10.

Liew E, Owen C . Familial myelodysplastic syndromes: a review of the literature. Haematologica. 2011; 96(10):1536-42. PMC: 3186316. DOI: 10.3324/haematol.2011.043422. View

11.

Balduini A, Malara A, Pecci A, Badalucco S, Bozzi V, Pallotta I . Proplatelet formation in heterozygous Bernard-Soulier syndrome type Bolzano. J Thromb Haemost. 2008; 7(3):478-84. DOI: 10.1111/j.1538-7836.2008.03255.x. View

12.

Weiss H, Meyer D, Rabinowitz R, Pietu G, Girma J, Vicic W . Pseudo-von Willebrand's disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers. N Engl J Med. 1982; 306(6):326-33. DOI: 10.1056/NEJM198202113060603. View

13.

Su Y, Wang Z, Yang H, Cao L, Liu F, Bai X . Clinical and molecular genetic analysis of a family with sitosterolemia and co-existing erythrocyte and platelet abnormalities. Haematologica. 2006; 91(10):1392-5. View

14.

Luo S, Mo X, Afshar-Kharghan V, Srinivasan S, Lopez J, Li R . Glycoprotein Ibalpha forms disulfide bonds with 2 glycoprotein Ibbeta subunits in the resting platelet. Blood. 2006; 109(2):603-9. PMC: 1785083. DOI: 10.1182/blood-2006-05-024091. View

15.

Chen Z, Naveiras O, Balduini A, Mammoto A, Conti M, Adelstein R . The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway. Blood. 2007; 110(1):171-9. PMC: 1896110. DOI: 10.1182/blood-2007-02-071589. View

16.

Ihara K, Ishii E, Eguchi M, Takada H, Suminoe A, GOOD R . Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci U S A. 1999; 96(6):3132-6. PMC: 15907. DOI: 10.1073/pnas.96.6.3132. View

17.

Morison I, Cramer Borde E, Cheesman E, Cheong P, Holyoake A, Fichelson S . A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nat Genet. 2008; 40(4):387-9. DOI: 10.1038/ng.103. View

18.

Noris P, Perrotta S, Seri M, Pecci A, Gnan C, Loffredo G . Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood. 2011; 117(24):6673-80. DOI: 10.1182/blood-2011-02-336537. View

19.

Savoia A, Pastore A, De Rocco D, Civaschi E, DI Stazio M, Bottega R . Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations. Haematologica. 2010; 96(3):417-23. PMC: 3046273. DOI: 10.3324/haematol.2010.032631. View

20.

Gandhi M, Cummings C, Drachman J . FLJ14813 missense mutation: a candidate for autosomal dominant thrombocytopenia on human chromosome 10. Hum Hered. 2003; 55(1):66-70. DOI: 10.1159/000071812. View