title: 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.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Mathildenstr 1, 79106 Freiburg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bartsch
authors.forename: Kirstin
authors.initials: K
authors.lastname: Sandrock
authors.forename: Francois
authors.initials: F
authors.lastname: Lanza
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.forename: Ina
authors.initials: I
authors.lastname: Hainmann
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlova
authors.forename: Andreas
authors.initials: A
authors.lastname: Greinacher
authors.forename: Uta
authors.initials: U
authors.lastname: Tacke
authors.forename: Michael
authors.initials: M
authors.lastname: Barth
authors.forename: Anja
authors.initials: A
authors.lastname: Busse
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Martin
authors.initials: M
authors.lastname: Bommer
authors.forename: Brigitte
authors.initials: B
authors.lastname: Strahm
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Barbara
authors.initials: B
authors.lastname: Zieger
mesh_terms: D001606:Bernard-Soulier Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D018797:Cell Cycle Proteins / Q000235:genetics*; D002675:Child, Preschool; D018572:Disease-Free Survival; D005089:Exocytosis / Q000235:genetics; D005164:Factor IX / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D054220:Malformations of Cortical Development; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D055571:Secretory Pathway / Q000235:genetics; D022142:Secretory Vesicles / Q000378:metabolism; D058112:Septins / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D005164:Factor IX; C109366:SEPTIN5 protein, human; D058112:Septins