A GP1BA Variant in a Czech Family with Monoallelic Bernard-Soulier Syndrome.
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ABSTRACT:
SUBMITTER: Skalnikova M
PROVIDER: S-EPMC8777725 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Classic Bernard-Soulier syndrome (BSS) is a rare form of autosomal recessive disorder that is caused by mutations in the GP1BA gene that encode the GPIb-V-IX complex, a receptor of von Willebrand factor. BSS characterized by macrothrombocytopenia and excessive bleeding. The present study reports a single case (18-month Chinese girl) diagnosed with BSS. The patient suffered mild thrombocytopenia, giant platelets and normal platelet aggregation. In addition, mild bleeding and thrombocytopenia were also indicated in thirteen family members, including the proband and her father. Gene sequence analysis identified a monoallelic missense mutation in GP1BA (c.97T>A), which encodes a p.C33R substitution in the N-terminal domain of glycoprotein (GP)Ibα that may disrupt the protein structure. To the best of our knowledge, this dominant variant has not been reported previously. BSS's autosomal dominant inheritance mode is rarely identified and can be easily misdiagnosed as immune thrombocytopenia. For patients with giant platelets, thrombocytopenia and positive family history, next-generation sequencing for inherited thrombocytopenia, especially disorders that are caused by mutations in glycoprotein Ib-IX-V complex, is required.
| S-EPMC7903392 | biostudies-literature
Project description:BACKGROUND: Bernard-Soulier syndrome (BSS) is a severe congenital bleeding disorder characterized by thrombocytopenia, thrombocytopathy and decreased platelet adhesion. BSS results from genetic alterations of the glycoprotein (GP) Ib/IX/V complex. METHODS: We report on a patient demonstrating typical BSS phenotype (thrombocytopenia with giant platelets, bleeding symptoms). However, BSS was not diagnosed until he reached the age of 39 years. RESULTS: Flow cytometry of the patient's platelets revealed absence of GPIb/IX/V receptor surface expression. In addition, immunofluorescence analysis of patient's platelets demonstrated very faint staining of GPIX. A novel homozygous deletion comprising 11 nucleotides starting at position 1644 of the GPIX gene was identified using molecular genetic analysis. CONCLUSIONS: The novel 11-nucleotide deletion (g.1644_1654del11) was identified as causing the bleeding disorder in the BSS patient. This homozygous deletion includes the last 4 nucleotides of the Kozak sequence as well as the start codon and the following 4 nucleotides of the coding sequence. The Kozak sequence is a region indispensable for the initiation of the protein translation process, thus preventing synthesis of functional GPIX protein in the case of deletion.
| S-EPMC2980512 | biostudies-literature
Project description:Bernard-Soulier syndrome (BSS), also known as Hemorrhagiparous thrombocytic dystrophy, is a hereditary bleeding disorder affecting the megakaryocyte/platelet lineage and characterized by bleeding tendency, giant blood platelets and low platelet counts. This syndrome is extremely rare as only approximately 100 cases have been reported in the literature. Clinical manifestations usually include purpura, epistaxis, menorrhagia, gingival and gastrointestinal bleeding. The syndrome is transmitted as an autosomal recessive trait. The underlying defect is a deficiency or dysfunction of the glycoprotein GPIb-V-IX complex, a platelet-restricted multisubunit receptor required for normal primary hemostasis. The GPIb-V-IX complex binds von Willebrand factor, allowing platelet adhesion and platelet plug formation at sites of vascular injury. Genes coding for the four subunits of the receptor, GPIBA, GPIBB, GP5 and GP9, map to chromosomes 17p12, 22q11.2, 3q29, and 3q21, respectively. Defects have been identified in GPIBA, GPIBB, and GP9 but not in GP5. Diagnosis is based on a prolonged skin bleeding time, the presence of a small number of very large platelets (macrothrombocytopenia), defective ristocetin-induced platelet agglutination and low or absent expression of the GPIb-V-IX complex. Prothrombin consumption is markedly reduced. The prognosis is usually good with adequate supportive care but severe bleeding episodes can occur with menses, trauma and surgical procedures. Treatment of bleeding or prophylaxis during surgical procedures usually requires platelet transfusion.
| S-EPMC1660532 | biostudies-literature
Project description:Background: Bernard-Soulier Syndrome (BSS) is a rare autosomal recessive bleeding disorder with large platelets and thrombocytopenia. It is caused by homozygous or compound heterozygous mutations in the GP1BA, GP1BB, or GP9 genes, which together encode the platelet surface receptor glycoprotein complex GPIb-IX-V. Objectives: We report two novel heterozygous mutations in the GP1BA and the GP9 genes, respectively. Patients/Methods: We analyzed the platelet glycoprotein expression by flow cytometry and screened the relevant genes for responsible mutations in two unrelated families. Results: Flow cytometric analyses revealed the absence of CD42a (GPIX) and CD42b (GPIb) on the platelets in the two affected siblings of family 1 and a significantly reduced expression of CD42b (GPIb) in the patient of family 2. In the two siblings, we identified a known frameshift (c.1601_1602delAT) and a novel nonsense mutation (c.1036C>T) in the GP1BA gene that abrogated the production of GP1bα. In the other patient, we found a novel missense mutation (c.112T>C) that was co-inherited with a common one (c.182A>G) in the GP9 gene, respectively. All analyzed heterozygous carriers were asymptomatic and had a normal GPIb-IX-V expression. Conclusions: The two novel GP1BA and GP9 mutations reported herein increment the number of causative genetic defects in BSS.
| S-EPMC7864212 | biostudies-literature
Project description:Bernard-Soulier syndrome (BSS) is a rare bleeding disorder of autosomal recessive inheritance characterized by macrothrombocytopenia. We report the case of a 14-year-old girl diagnosed with BSS who is a fourth-generation Brazilian of Japanese descent and has a compound heterozygote mutation as the responsible gene. The compound heterozygosity would have occurred from the global and long-term racial migration that brought about an accidental encounter of two rare mutant alleles of different origins.
| S-EPMC5529668 | biostudies-literature
Project description:BackgroundBernard-Soulier syndrome is a severe bleeding disease due to a defect of GPIb/IX/V, a platelet complex that binds the von Willebrand factor. Due to the rarity of the disease, there are reports only on a few cases compromising any attempt to establish correlations between genotype and phenotype. In order to identify any associations, we describe the largest case series ever reported, which was evaluated systematically at the same center.Design and methodsThirteen patients with the disease and seven obligate carriers were enrolled. We collected clinical aspects and determined platelet features, including number and size, expression of membrane glycoproteins, and ristocetin induced platelet aggregation. Mutations were identified by direct sequencing of the GP1BA, GP1BB, and GP9 genes and their effect was shown by molecular modeling analyses.ResultsPatients all had a moderate thrombocytopenia with giant platelets and a bleeding tendency whose severity varied among individuals. Consistent with expression levels of GPIbα always lower than 10% of control values, platelet aggregation was absent or severely reduced. Homozygous mutations were identified in the GP1BA, GP1BB and GP9 genes; six were novel alterations expected to destabilize the conformation of the respective protein. Except for obligate carriers of a GP9 mutation with a reduced GPIb/IX/V expression and defective aggregation, all the other carriers had no obvious anomalies.ConclusionsRegardless of mutations identified, the patients' bleeding diathesis did not correlate with thrombocytopenia, which was always moderate, and platelet GPIbα expression, which was always severely impaired. Obligate carriers had features similar to controls though their GPIb/IX/V expression showed discrepancies. Aware of the limitations of our cohort, we cannot define any correlations. However, further investigations should be encouraged to better understand the causes of this rare and underestimated disease.
| S-EPMC3046273 | biostudies-literature
Project description:The management of patients with coagulopathic disorders undergoing orthopaedic surgery requires a dedicated, multi-disciplinary team with detailed perioperative planning. Bernard-Soulier Syndrome (BSS) is an extremely rare disorder, affecting 1 in 1 million individuals worldwide. It is caused by a deficiency in glycoprotein 1b-V-IX which is required for normal platelet-mediated clot formation. The deficiency results in prolonged bleeding time with high risk of spontaneous bleeds. Few reports exist in the clinical literature of BSS patients undergoing major surgery.A 40 year old, female with known BSS and developmental dysplasia of her left hip (DDH) was referred to us for consideration of left total hip arthroplasty (THA). Consultation with her Haematologist for pre-operative optimization of platelets and related clotting times together with detailed discussions of her intended anaesthesia protocol and surgery resulted in a successful operation with less than anticipated blood loss. She entered our rehabilitation program just one week after surgery.BSS is an extremely rare bleeding disorder that puts patients at very high risk of blood loss following surgery. This is the first report that we are aware of describing a BSS patient undergoing a THA. A cohesive, highly specialized, multi-disciplinary team is crucial to the success of these patients.
| S-EPMC4719372 | biostudies-other
Project description:Bernard-Soulier syndrome (BSS) is an inherited bleeding disorder caused by a defect in the platelet glycoprotein (GP) Ib-IX-V complex. The main treatment for BSS is platelet transfusion but it is often limited to severe bleeding episodes or surgical interventions due to the risk of alloimmunization. We have previously reported successful expression of human GPIbα (hGPIbα) in human megakaryocytes using a lentiviral vector (LV) encoding human GP1BA under control of the platelet-specific integrin αIIb promoter (2bIbα). In this study, we examined the efficacy of this strategy for the gene therapy of BSS using GPIbα(null) as a murine model of BSS. GPIbα(null) hematopoietic stem cells (HSC) transduced with 2bIbα LV were transplanted into lethally irradiated GPIbα(null) littermates. Therapeutic levels of hGPIbα expression were achieved that corrected the tail bleeding time and improved the macrothrombocytopenia. Sequential bone marrow (BM) transplants showed sustained expression of hGPIbα with similar phenotypic correction. Antibody response to hGPIbα was documented in 1 of 17 total recipient mice but was tolerated without any further treatment. These results demonstrate that lentivirus-mediated gene transfer can provide sustained phenotypic correction of murine BSS, indicating that this approach may be a promising strategy for gene therapy of BSS patients.
| S-EPMC3293608 | biostudies-other
Project description:The human Bernard-Soulier syndrome is an autosomal recessive disorder of platelet dysfunction presenting with mild thrombocytopenia, circulating "giant" platelets and a bleeding phenotype. The bleeding in patients with the Bernard-Soulier syndrome is disproportionately more severe than suggested by the reduced platelet count and is explained by a defect in primary hemostasis owing to the absence of the platelet glycoprotein (GP) Ib-IX-V membrane receptor. However, the molecular basis for the giant platelet phenotype and thrombocytopenia have remained unresolved but assumed to be linked to an absent receptor complex. We have disrupted the gene encoding the alpha-subunit of mouse GP Ib-IX-V (GP Ibalpha) and describe a murine model recapitulating the hallmark characteristics of the human Bernard-Soulier syndrome. The results demonstrate a direct link between expression of a GP Ib-IX-V complex and normal megakaryocytopoiesis and platelet morphogenesis. Moreover, using transgenic technology the murine Bernard-Soulier phenotype was rescued by expression of a human GP Ibalpha subunit on the surface of circulating mouse platelets. Thus, an in vivo model is defined for analysis of the human GP Ib-IX-V receptor and its role in the processes performed exclusively by megakaryocytes and platelets.
| S-EPMC16010 | biostudies-literature
Project description:Bernard-Soulier syndrome (BSS) is a rare congenital disease characterized by macrothrombocytopenia and frequent bleeding. It is caused by pathogenic variants in three genes (GP1BA, GP1BB, or GP9) that encode for the GPIbα, GPIbβ, and GPIX subunits of the GPIb-V-IX complex, the main platelet surface receptor for von Willebrand factor, being essential for platelet adhesion and aggregation. According to the affected gene, we distinguish BSS type A1 (GP1BA), type B (GP1BB), or type C (GP9). Pathogenic variants in these genes cause absent, incomplete, or dysfunctional GPIb-V-IX receptor and, consequently, a hemorrhagic phenotype. Using gene-editing tools, we generated knockout (KO) human cellular models that helped us to better understand GPIb-V-IX complex assembly. Furthermore, we developed novel lentiviral vectors capable of correcting GPIX expression, localization, and functionality in human GP9-KO megakaryoblastic cell lines. Generated GP9-KO induced pluripotent stem cells produced platelets that recapitulated the BSS phenotype: absence of GPIX on the membrane surface and large size. Importantly, gene therapy tools reverted both characteristics. Finally, hematopoietic stem cells from two unrelated BSS type C patients were transduced with the gene therapy vectors and differentiated to produce GPIX-expressing megakaryocytes and platelets with a reduced size. These results demonstrate the potential of lentiviral-based gene therapy to rescue BSS type C.
| S-EPMC10320622 | biostudies-literature