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A A386G biallelic GPIb? gene mutation with anomalous behavior: a new mechanism suggested for Bernard-Soulier syndrome pathogenesis.

ABSTRACT: Platelet glycoprotein GPIb? mutations are the basic defect behind Bernard-Soulier syndrome, a rare inherited macrothrombocytopenia characterized by anomalies of the GPIb?, GPIb? and GPIX subunits of von Willebrand factor receptor. A 32-year old man was investigated for suspected Bernard-Soulier syndrome. Ristocetin induced agglutination was absent. Flow cytometry and Western blot analysis showed a severe reduction in GPIb?, but sequencing revealed only a biallelic c.386A>G substitution, theoretically leading to a p.Asn110Glu variation. To further clarify the data, megakaryocyte cultures were set. Though the maturation of megakaryocytes was normal, proplatelet formation was defective and GPIb? mRNA was not detectable. GPIX protein was slightly reduced and GPIb? polypeptide almost absent. Computational analysis showed that the c.386A>G mutation disrupted an exon splicing enhancer motif involved in the proper maturation of the GPIb? transcript. The c.386A>G mutation suggests a unique mutational mechanism causing the virtual absence of GPIb? without creating a stop codon.

SUBMITTER: Vettore S

PROVIDER: S-EPMC3232274 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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A A386G biallelic GPIbα gene mutation with anomalous behavior: a new mechanism suggested for Bernard-Soulier syndrome pathogenesis.

Vettore Silvia S Tezza Fabiana F Malara Alessandro A Vianello Fabrizio F Pecci Alessandro A Scandellari Raffaella R Floris Matteo M Balduini Alessandra A Fabris Fabrizio F

Haematologica 20111011 12

Platelet glycoprotein GPIbα mutations are the basic defect behind Bernard-Soulier syndrome, a rare inherited macrothrombocytopenia characterized by anomalies of the GPIbα, GPIbβ and GPIX subunits of von Willebrand factor receptor. A 32-year old man was investigated for suspected Bernard-Soulier syndrome. Ristocetin induced agglutination was absent. Flow cytometry and Western blot analysis showed a severe reduction in GPIbα, but sequencing revealed only a biallelic c.386A>G substitution, theoreti ...[more]

PMID: 21993687

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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.

Dataset Information

A A386G biallelic GPIb? gene mutation with anomalous behavior: a new mechanism suggested for Bernard-Soulier syndrome pathogenesis.

Publications

A A386G biallelic GPIbα gene mutation with anomalous behavior: a new mechanism suggested for Bernard-Soulier syndrome pathogenesis.

Similar Datasets

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