Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome

2004 ◽  
Vol 78 (1) ◽  
pp. 41-48 ◽  
Author(s):  
Jeanne Drouin ◽  
Nancy L. Carson ◽  
Odette Laneuville
Keyword(s):  
Missense Mutation ◽  
Compound Heterozygosity ◽  
Nucleotide Deletion ◽  
Bernard Soulier Syndrome

Identification of Inherited Macrothrombocytopenias Based on Mean Platelet Volume among Patients Diagnosed with Idiopathic Thrombocytopenia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3981-3981
Author(s):  
Fumito Gohda ◽  
Hideki Uchiumi ◽  
Hiroshi Handa ◽  
Matsushima Takafumi ◽  
Norifumi Tsukamoto ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Steroid Therapy ◽  
Mean Platelet Volume ◽  
Two Dimensional ◽  
Platelet Volume ◽  
Giant Platelets ◽  
Idiopathic Thrombocytopenia ◽  
Related Disease ◽  
Advia 120 ◽  
Bernard Soulier Syndrome

Abstract Inherited macrothrombocytopenia is a rare illness that is often misdiagnosed as idiopathic thrombocytopenia (ITP), a more widespread acquired disease. The hallmark of a diagnosis of these diseases is the presence of giant platelets. Automated blood cell counters in routine clinical use usually miss giant platelets and underestimate mean platelet volume (MPV). Incorrect diagnoses might expose patients to a risk of unnecessary treatment. The ADVIA 120 hematology counter efficiently detects large platelets based on two-dimensional laser light scatter. This two-dimensional approach provides a more accurate estimation of platelet volume than conventional one-dimensional analysis. The present study measures and re-evaluates MPV using the ADVIA 120 in 112 patients who had initially been diagnosed with ITP. We identified 11 unrelated patients as having probable macrothrombocytopenia (average MPV of 19.2 ± 3.8 fL; normal range 7.8–10.2). A diagnosis of inherited macrothrombocytopenia was immediately ruled out in 5 of the 11 patients, because their medical records indicated that their platelet counts had once been normal or became normalized (>100x199/L) in response to steroid therapy. Of the remaining 6 patients, platelets aggregated abnormally in response to ristocetin in 3 patients and MYH9-RD was suspected in one patient since Döhle-like bodies were apparent in granulocytes on blood films. DNA analyses confirmed that 3 of these patients had Bernard-Soulier syndrome and 1 had MYH9-related disease, both of which are the most common forms of inherited macrothrombocytopenia. We detected 3 homozygous mutations in the 3 patients with Bernard-Soulier syndrome: A3171T and 4444insT in the GPIbα gene that created new premature termination codons, and the missense mutation, G1913A in the GPIX gene, that caused the loss of GPIX surface expression. In one patient with MYH9-related disease, we found a heterozygous missense mutation of C5797T in exon 40 of the MYH9 gene. We stress that all four patients had received high-dose steroid therapy and/or splenectomy before this study according to a diagnosis of ITP. Checking MPV using the ADVIA 120 in thrombocytopenic patients is a useful method of correctly diagnosing inherited macrothrombocytopenia, and thus avoiding patient exposure to unnecessary and sometimes toxic treatment.

Bernard-Soulier Syndrome due to Compound Heterozygosity for a Novel Glycoprotein Ib� Mutation

2014 ◽  
Vol 131 (1) ◽  
pp. 46-49 ◽  
Author(s):  
Tetsuji Sato ◽  
Shinji Kunishima ◽  
Rie Shirayama ◽  
Shun Ichikawa ◽  
Michio Sakai ◽  
...  
Keyword(s):  
Compound Heterozygosity ◽  
Glycoprotein Ib ◽  
Bernard Soulier Syndrome

The Critical Interaction of Glycoprotein (GP) Ibβ With GPIX—A Genetic Cause of Bernard-Soulier Syndrome

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 2968-2975 ◽  
Author(s):  
Dermot Kenny ◽  
Patricia A. Morateck ◽  
Joan C. Gill ◽  
Robert R. Montgomery
Keyword(s):  
Amino Acids ◽  
Chinese Hamster Ovary Cells ◽  
Surface Expression ◽  
Platelet Glycoprotein ◽  
Wild Type ◽  
Single Nucleotide ◽  
Platelet Surface ◽  
Single Nucleotide Deletion ◽  
Nucleotide Deletion ◽  
Bernard Soulier Syndrome

Bernard-Soulier syndrome is an uncommon bleeding disorder caused by a quantitative or qualitative defect in the platelet glycoprotein (GP)Ib/IX complex. The complex is composed of four subunits, GPIb, GPIbβ, GPIX, and GPV. Here we describe the molecular basis of a novel Bernard-Soulier syndrome variant in a patient in whom GPIb and GPIX were undetectable on the platelet surface. DNA sequence analysis showed normal sequence for GPIb, GPIX, and GPV. The GPIbβ gene has been mapped to the 22q11.2 region of chromosome 22 which was deleted from one chromosome of this patient. There was a single nucleotide deletion within the codon for Ala 80 in GPIbβ within the other allele. This mutation causes a translational frame shift that encodes for 86 altered amino acids and predicts a premature stop 15 amino acids short of the length of the wild-type protein. Transient coexpression of the mutant GPIbβ in 293T cells with wild-type GPIb and GPIX resulted in the surface expression of GPIb, but the absence of GPIX. Moreover, when a plasmid encoding the wild-type GPIbβ was transiently transfected into Chinese hamster ovary cells stably expressing GP, which retain the capacity to reexpress GPIX, there was a significant increase in the surface expression of GPIX. In contrast, when the mutant GPIbβ was transiently transfected into these cells, GPIX was not reexpressed on the plasma surface. Thus, a deletion of one copy of GPIbβ and a single nucleotide deletion in the codon for Ala 80 within the remaining GPIbβ allele causes the Bernard-Soulier phenotype through an interaction of GPIbβ with GPIX resulting in the absence of GPIb on the plasma membrane. The interaction of GPIbβ with GPIX is essential for the functional expression of GPIb.

Compound heterozygosity of a paternal submicroscopic deletion and a maternal missense mutation inPORgene: Antley-bixler syndrome phenotype in three sibling fetuses

2016 ◽  
Vol 106 (7) ◽  
pp. 536-541 ◽  
Author(s):  
Maria Tzetis ◽  
Anastasia Konstantinidou ◽  
Christalena Sofocleous ◽  
Konstantina Kosma ◽  
Anastasios Mitrakos ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Compound Heterozygosity ◽  
Submicroscopic Deletion

The Critical Interaction of Glycoprotein (GP) Ibβ With GPIX—A Genetic Cause of Bernard-Soulier Syndrome

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 2968-2975 ◽  
Author(s):  
Dermot Kenny ◽  
Patricia A. Morateck ◽  
Joan C. Gill ◽  
Robert R. Montgomery
Keyword(s):  
Amino Acids ◽  
Chinese Hamster Ovary Cells ◽  
Surface Expression ◽  
Platelet Glycoprotein ◽  
Wild Type ◽  
Single Nucleotide ◽  
Platelet Surface ◽  
Single Nucleotide Deletion ◽  
Nucleotide Deletion ◽  
Bernard Soulier Syndrome

Abstract Bernard-Soulier syndrome is an uncommon bleeding disorder caused by a quantitative or qualitative defect in the platelet glycoprotein (GP)Ib/IX complex. The complex is composed of four subunits, GPIb, GPIbβ, GPIX, and GPV. Here we describe the molecular basis of a novel Bernard-Soulier syndrome variant in a patient in whom GPIb and GPIX were undetectable on the platelet surface. DNA sequence analysis showed normal sequence for GPIb, GPIX, and GPV. The GPIbβ gene has been mapped to the 22q11.2 region of chromosome 22 which was deleted from one chromosome of this patient. There was a single nucleotide deletion within the codon for Ala 80 in GPIbβ within the other allele. This mutation causes a translational frame shift that encodes for 86 altered amino acids and predicts a premature stop 15 amino acids short of the length of the wild-type protein. Transient coexpression of the mutant GPIbβ in 293T cells with wild-type GPIb and GPIX resulted in the surface expression of GPIb, but the absence of GPIX. Moreover, when a plasmid encoding the wild-type GPIbβ was transiently transfected into Chinese hamster ovary cells stably expressing GP, which retain the capacity to reexpress GPIX, there was a significant increase in the surface expression of GPIX. In contrast, when the mutant GPIbβ was transiently transfected into these cells, GPIX was not reexpressed on the plasma surface. Thus, a deletion of one copy of GPIbβ and a single nucleotide deletion in the codon for Ala 80 within the remaining GPIbβ allele causes the Bernard-Soulier phenotype through an interaction of GPIbβ with GPIX resulting in the absence of GPIb on the plasma membrane. The interaction of GPIbβ with GPIX is essential for the functional expression of GPIb.

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