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Genetics of Inherited Disorders of Platelets

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Genetics of Inherited Disorders of Platelets Bleeding disorders Genetics of inherited disorders of platelets A.T. Nurden1 ABSTRACT P. Nurden1,2 Genetic defects of platelets constitute a group of rare diseases that give rise to bleeding syndromes of autosomal dominant or recessive inheritance. They affect platelet production, giving rise to a low 1Plateforme Technologique et circulating platelet count and changes in platelet morphology, platelet function, or a combination of d’Innovation Biomédicale, Hôpital both an altered megakaryopoiesis and a defective platelet response. As a result, blood platelets fail to Xavier Arnozan, Pessac; fulfill their hemostatic function. The most studied are deficiencies of glycoprotein mediators of adhe- 2CHU Timone, Marseille, France sion and aggregation while defects of primary receptors for stimuli include that of the P2Y12 ADP receptor. Inherited defects of secretion from storage organelles (dense granules, α-granules) and of Correspondence: the generation of procoagulant activity have led to the identification of many genes involved in Alan T. Nurden megakaryocyte biology. Signaling pathway defects leading to agonist-specific modifications of E-mail: [email protected] platelet aggregation are the current target of exome-sequencing strategies. In familial thrombocy- topenia, changes in megakaryocyte maturation within the bone marrow mostly lead to a deficient pro- platelet formation and an altered timing of platelet release; sometimes defects extend to other cells Hematology Education: and in some cases interfere with development. We now review recent advances in the field and high- the education program for the light genes responsible for inherited diseases of platelets. annual congress of the European Hematology Association Learning goals 2013;7:67-78 At the conclusion of this activity, participants should be able to assess: - how a wide variety of molecular defects of surface and intracellular constituents of platelets lead to defective platelet function and bleeding; - how pathologies within each of a series of major gene families put inherited disorders of platelets to the forefront of research into rare diseases; - how genetic defects of transcription factors and of cytoskeletal proteins can affect megakaryocyte biology leading to an altered platelet morphology and number; - how the use of modern gene screening procedures including whole exome or genome sequencing will transform practice in a routine hematology laboratory. The Human Genome Variation Society (HGVS) numbering and nomenclature as used in this review (available from://www.Hgvs.org/mutnomen) is recommended to describe mutations. Since amino acid numbering within each protein is now recommended to start with the initiating methionine, while it was variably used before, current numbering is often different from the one used in the original publications. In cases in which the HGVS numbering is different from the original publica- tions, the original nomenclature is provided in parentheses. Introduction association and genome-wide association studies should also be born in mind for they This review of inherited disorders of platelet can cumulatively lead to hypo-reactive function and platelet production will empha- platelets and affect such parameters as platelet size recent advances and the identification of size or count. TheyPEAR1 include novel gene vari- genes whose defects are at the origin of a ants such as (platelet endothelial bleeding syndrome.1-4 Spontaneous bleeding is aggregation receptor 1) that modulate platelet mostly mucocutaneous in nature; excessive reactivity and bleeding tendency.45-48 trauma-related bleeding is another feature of milder forms. Treatment has been reviewed 5 Defects of platelet function elsewhere. Figure 1 illustrates disorders affecting platelet surface constituents, while Defects of platelet adhesion Figure 2 shows those affecting intracellular Abnormalities of GPIb-IX function. components. Tables 1 and 2 summarize gene defects giving familial thrombocytopenia (FT) Bernard-Soulier syndrome (BSS) associates a with or without defects of platelet function and moderate to severe macrothrombocytopenia grouped according to platelet morphology. with a decreased von Willebrand factor Gene variants identified by candidate gene (VWF)-dependent platelet adhesion under Hematology Education: the education program for the annual congress of the European Hematology Association | 2013; 7(1) | 67 | 18th Congress of the European Hematology Association flow caused by quantitative or qualitative defects of GPIb- the membrane cytoskeleton may account for the giant IX-V (Table 1). GPIbα contains VWF and thrombin-bind- platelets. In rare variant BSS, platelets express non-func- ing sites within the N-terminal domain. The additional tional GPIbα.1,2,4 A common heterozygous p.Ala172Val absence of extracellular binding sites on GPIbα for P- (formerly Ala156Val) mutation is the cause of inherited α β 8 selectin, TSP1, coagulation factors (F) XI and XII, M 2 thrombocytopeniaGPIBB alone in Southern Italy. Heterozygous and high molecular weight kininogen may extend the phe- mutations in cause BSS when associated with the 6 GPIBA GPIBB GP9 notype.GP5The products of four genes ( , , DiGeorge/velocardiofacial syndrome, a developmental and ) assemble in a 2:4:2:1 ratio within maturing disorder given by a heterozygousGPIBB microdeletion at 22q11, megakaryocytes (MK) in the bone marrow to form GPIb- the site of localization of . Correction of murine IX-V as present in the platelet membrane.6 Mutations BSS by lentivirus-mediated gene therapy suggests a prom- GPIBA GPIBB GP9 49 within , and in BSS prevent the com- isingUpregulated strategy for VWF-binding gene therapy. to GPIb . position and/or trafficking of the complex through the α Platelet-type von endoplasmic reticulum (ER) and Golgi apparatus by Willebrand disease (platelet-type VWD) is characterized changing the quaternary organization of GPIb-IX.7 The by thrombocytopenia and increased platelet agglutination absence of the interaction between GPIbα and filamin A in by low-dose ristocetin in the presence of normal plasma. Table 1. Inherited thrombocytopenia with large-sized platelets. Group of Syndrome Platelet count Platelet Associated Associated biological Gene defect and Ref abnormalities and morphology function phenotype abnormalities transmission Platelet adhesion BSS Moderate to severe decrease Loss of platelet Occasionally Impaired platelet GPIBA (17p13) 6-8 Giant platelets adhesion to VWF Di-George syndrome production GPIBB (22q11) GP9 (3q21) AR Platelet-type VWD Decreased Enhanced VWF/GPIb. - Blocked GPIb GPIBA (17p13) 2,9,10 Some large platelets Abnormal vessel-wall Loss of large AD interaction VWF multimers from plasma VWD2B Variable, Enhanced VWF/GPIb - Abnomal VWF Exon 28 of VWF 2,11 +/- enlarged, sometimes Abnormal vessel-wall Loss of large (12p13.3) agglutinated platelets interaction VWF multimers from plasma AD Transcription factors GATA-1 Decreased Aggregation impaired, Dyserythropoietic anemia, Decreased protein GATA-1 2,12,13 Enlarged platelets β-thalassemia (e.g. GPIb-IX) and (Xp11) α-granule expression X-linked Paris-Trousseau Decreased with giant - Psychomotor retardation, Immature MKs predominate FLI1 (11q23.3) 2,12,14,15 syndrome fused granules facial, cardiac defects in marrow microdeletion AD α-granule defects Gray platelet Decreased with enlarged Variable aggregation Myelofibrosis Occasional loss of GPVI NBEAL2 16-20 syndrome platelets lacking response Enlarged spleen Increased Vitamin B12 (3p21) α-granules mostly AR Quebec syndrome Sometimes decreased Abnormal response Excessive fibrinolysis Proteolytic degradation PLAU 21,22 Platelet aniscocytosis to epinephrine of α-granule proteins (10q24) tandem duplication Cytoskeleton defects MYH9-RD Decreased Abnormal NMMHC-IIA Deafness, Presence of Döhle MYH9 2,12, Presence of giant platelets distribution and function cataract, bodies in leukocytes (22q12-13) 23,24 renal dysfunction AD Filaminopathia Decreased Abnormal thrombus Neurological, Abnormal distribution FLNA 2,25,26 Variable presence formation gastro-intestinal, of FLNA in platelets (Xq28) of large platelets cardiologic X-linked Tubulin 1 Decreased Normal aggregation - Platelets with TBB1 12,27 Presence of large, decreased microtubules (6p21.3) round, platelets AD Defects of αIIbβ3 Isolated Decreased Variable aggregation - Altered platelet production ITGA2B 28-31 thrombocytopenia Presence of large platelets response ITGB3 (17q21.32) AD or AR Lipid metabolic Hyperabsorption and Normal at birth, Reduced Premature coronary Increased plant sterols, ABCG5 or ABCG8 12,32 disorder defect of metabolism rapidly artery disease and hypercholesterolemia (2p21) of sterols macrothrombocytopenic atherosclerotic disease AR | 68 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2013; 7(1) Stockholm, Sweden, June 13-16, 2013 p.Gly249Val (or Ser), p.Asp251Tyr, p.Met255Val (previ- sity of both receptors and affect the collagen response.45 ously Gly233Val/Ser, Asp235Tyr, Met239Val) substitu- ANKRD26Patients with FT linked to heterozygous mutations in the tions provoke changes in the conformation of the GPIbα (ankyrin repeat domain 26) gene variably N-terminal domain that binds soluble VWF directly as express α2β1, otherwise there is no clear pathology of this 51 does a p.Pro449_Ser457GPIBA deletion in the macroglycopep- integrin. In contrast, individuals in two families with a tide-coding region of .4,9,10 This clinical condition life-long
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