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DOI: 10.1160/TH11-05-0305
Deletion of human GP1BB and SEPT5 is associated with Bernard-Soulier syndrome, platelet secretion defect, polymicrogyria, and developmental delay
Financial support: This work was supported by a DFG Grant (ZI 486/4–1).Publikationsverlauf
Received: 05. Mai 2011
Accepted after major revision: 17. Juni 2011
Publikationsdatum:
24. November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201103/lookinside/thumbnails/10-1160-th11-05-0305-1.jpg)
Summary
The bleeding disorder Bernard-Soulier syndrome (BSS) is caused by mutations in the genes coding for the platelet glycoprotein GPIb/IX receptor. The septin SEPT5 is important for active membrane movement such as vesicle trafficking and exocytosis in non-dividing cells (i.e. platelets, neurons). We report on a four-year-old boy with a homozygous deletion comprising not only glycoprotein Ibβ (GP1BB) but also the SEPT5 gene, located 5’ to GP1BB. He presented with BSS, cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect. The homozygous deletion of GP1BB and SEPT5, which had been identified by PCR analyses, was confirmed by Southern analyses and denaturing HPLC (DHPLC). The parents were heterozygous for this deletion. Absence of GPIbβ and SEPT5 proteins in the patient’s platelets was illustrated using transmission electron microscopy. Besides decreased GPIb/IX expression, flow cytometry analyses revealedimpaired platelet granule secretion. Because the bleeding disorder was extremely severe, the boy received bone marrow transplantation (BMT) from a HLA-identical unrelated donor. After successful engraftment of BMT, he had no more bleedingepisodes. Interestingly, also his mental development improved strikingly after BMT. This report describes for the first time a patient with SEPT5 deficiency presenting with cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect.
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References
- 1 Lanza F. Bernard-Soulier syndrome (hemorrhagiparous thrombocytic dystrophy). Orphanet J Rare Dis 2006; 1: 46.
- 2 Zieger B, Hashimoto Y, Ware J. Alternative expression of platelet glycoprotein Ib(beta) mRNA from an adjacent 5’ gene with an imperfect polyadenylation signal sequence. J Clin Invest 1997; 99: 520-525.
- 3 Macara IG, Baldarelli R, Field CM. et al. Mammalian septins nomenclature. Mol Biol Cell 2002; 13: 4111-4113.
- 4 Kinoshita M, Noda M. Roles of septins in the mammalian cytokinesis machinery. Cell Struct Funct 2001; 26: 667-670.
- 5 Hsu SC, Hazuka CD, Roth R. et al. Subunit composition, protein interactions, and structures of the mammalian brain sec6/8 complex and septin filaments. Neuron 1998; 20: 1111-1122.
- 6 Roeseler S, Sandrock K, Bartsch I. et al. Septins, a novel group of GTP-binding proteins: relevance in hemostasis, neuropathology and oncogenesis. Klin Padiatr 2009; 221: 150-155.
- 7 Dent J, Kato K, Peng XR. et al. A prototypic platelet septin and its participation in secretion. Proc Natl Acad Sci USA 2002; 99: 3064-3069.
- 8 Blaser S, Horn J, Wurmell P. et al. The novel human platelet septin SEPT8 is an interaction partner of SEPT4. Thromb Haemost 2004; 91: 959-966.
- 9 Martinez C, Corral J, Dent JA. et al. Platelet septin complexes form rings and associate with the microtubular network. J Thromb Haemost 2006; 4: 1388-1395.
- 10 Suzuki G, Harper KM, Hiramoto T. et al. Sept5 deficiency exerts pleiotropic influence on affective behaviors and cognitive functions in mice. Hum Mol Genet 2009; 18: 1652-1660.
- 11 McDermid HE, Morrow BE. Genomic disorders on 22q11. Am J Hum Genet 2002; 70: 1077-1088.
- 12 Budarf ML, Konkle BA, Ludlow LB. et al. Identification of a patient with Bernard-Soulier syndrome and a deletion in the DiGeorge/velo-cardio-facial chromosomal region in 22q11.2. Hum Mol Genet 1995; 4: 763-766.
- 13 Kato T, Kosaka K, Kimura M. et al. Thrombocytopenia in patients with 22q11.2 deletion syndrome and its association with glycoprotein Ib-beta. Genet Med 2003; 5: 113-119.
- 14 Jurk K, Schulz AS, Kehrel BE. et al. Novel integrin-dependent platelet malfunction in siblings with leukocyte adhesion deficiency-III (LAD-III) caused by a point mutation in FERMT3. Thromb Haemost 2010; 103: 1053-1064.
- 15 Nurden P, Poujol C, Winckler J. et al. Immunolocalization of P2Y1 and TPalpha receptors in platelets showed a major pool associated with the membranes of alpha -granules and the open canalicular system. Blood 2003; 101: 1400-1408.
- 16 Zieger B, Tran H, Hainmann I. et al. Characterization and expression analysis of two human septin genes, PNUTL1 and PNUTL2. Gene 2000; 261: 197-203.
- 17 Poujol C, Ware J, Nieswandt B. et al. Absence of GPIbalpha is responsible for aberrant membrane development during megakaryocyte maturation: ultrastructural study using a transgenic model. Exp Hematol 2002; 30: 352-360.
- 18 Schneider W, Schnaidt M. The platelet adhesion immunofluorescence test: a modification of the platelet suspension immunofluorescence test. Blut 1981; 43: 389-392.
- 19 Pavlova A, El-Maarri O, Luxembourg B. et al. Detection of heterozygous large deletions in the antithrombin gene using multiplex polymerase chain reaction and denatured high performance liquid chromatography. Haematologica 2006; 91: 1264-1267.
- 20 Zieger B, Jenny A, Tsakiris DA. et al. A large Swiss family with Bernard-Soulier syndrome – Correlation phenotype and genotype. Hamostaseologie 2009; 29: 161-167.
- 21 Kato K, Martinez C, Russell S. et al. Genetic deletion of mouse platelet glycoprotein Ibbeta produces a Bernard-Soulier phenotype with increased alpha-granule size. Blood 2004; 104: 2339-2344.
- 22 Strassel C, Nonne C, Eckly A. et al. Decreased thrombotic tendency in mouse models of the Bernard-Soulier syndrome. Arterioscler Thromb Vasc Biol 2007; 27: 241-247.
- 23 Gothelf D, Schaer M, Eliez S. Genes, brain development and psychiatric phenotypes in velo-cardio-facial syndrome. Dev Disabil Res Rev 2008; 14: 59-68.
- 24 Beites CL, Xie H, Bowser R. et al. The septin CDCrel-1 binds syntaxin and inhibits exocytosis. Nat Neurosci 1999; 2: 434-439.
- 25 Robin NH, Taylor CJ, McDonald Mc, Ginn DM. et al. Polymicrogyria and deletion 22q11.2 syndrome: window to the etiology of a common cortical malformation. Am J Med Genet A 2006; 140: 2416-2425.
- 26 van Essen DC. A tension-based theory of morphogenesis and compact wiring in the central nervous system. Nature 1997; 385: 313-318.
- 27 Xie Y, Vessey JP, Konecna A. et al. The GTP-binding protein Septin 7 is critical for dendrite branching and dendritic-spine morphology. Curr Biol 2007; 17: 1746-1751.
- 28 Balduini CL, Iolascon A, Savoia A. Inherited thrombocytopenias: from genes to therapy. Haematologica 2002; 87: 860-880.