Deletion of human GP1BB and SEPT5 is associated with Bernard-Soulier syndrome, platelet secretion defect, polymicrogyria, and developmental delay

Abstract

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 revealed impaired 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 bleeding episodes. 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.

Phosphoproteomic Analysis of Platelets Activated by Pro-Thrombotic Oxidized Phospholipids and Thrombin

“…The analysis of our data revealed numerous phosphorylation events that occurred in proteins whose platelet-related function has just recently been recognized or is not known indicating the discovery aspect of the approach and the relevance of the results. For example, both agonists studied induced significant changes in phosphorylation sites of SEPT5 and FERMT3, and deficiency of these proteins causes bleeding disorders associated with platelet defects [41], [42]. Also, KODA-PC induced dephosphorylation of LRRFIP1 at Ser115, a protein with variations in human platelets that affects platelet reactivity and is associated with myocardial infarction [43].…”

Septin functions in organ system physiology and pathology

“…Mice lacking the GpIBB gene exhibit symptoms that phenocopy BSS pathology and possess platelets with abnormally large α-granules and elevated levels of SEPT5 (Kato et al, 2004). More recently, genotypic analysis of a juvenile patient with a severe case of BBS showed homozygous deletions of the GpIBB and SEPT5 genes, which are positioned directly next to each other (Zieger et al, 1997; Bartsch et al, 2011). …”

Sep(t)arate or not – how some cells take septin-independent routes through cytokinesis

“…However, subsequent studies revealed that, although neurotransmitter release is unaltered in Sept5 −/− mice, platelet degranulation is deregulated (Dent et al, 2002;Peng et al, 2002). In addition, clinically, Sept5 deletion is associated with Bernard-Soulier syndrome (BSS), a bleeding disorder arising from platelet dysfunction (Bartsch et al, 2011). Another septin function emerged from work showing that the interaction between SEPT7 and CD2AP facilitates the exocytosis of glucose transporter GLUT4 storage granules in kidney epithelial cells (Wasik et al, 2012).…”