Identification of a new mutation in platelet glycoprotein IX (GPIX) in a patient with Bernard–Soulier syndrome

Rivera, Candido E.; Villagra, José; Riordan, Michael; Williams, Sybil B.; Lindstrom, Katarina J.; Rick, Margaret E.

doi:10.1046/j.1365-2141.2001.02529.x

Cited by 27 publications

(22 citation statements)

References 8 publications

(8 reference statements)

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“…Of the eight alterations, six were novel mutations, including two frameshift duplications c.491dupA and c.442dupG in GP1BB and GP9, respectively and four amino acid substitutions, p.Asn126Asp in GP1BA and p.Cys24Trp, p.Leu63Pro, and p.Tyr95Cys in GP9. Of note, mutations at Cys24 corresponded to different substitutions: in families F4 and F5, as previously reported, 19 we observed a c.70T>C substitution which corresponds to a p.Cys24Arg substitution whereas in family F6 we identified the 70T>C mutation, which leads to p.Cys24Trp. All four amino acid substitutions affect residues that are well conserved during evolution (Online Supplementary Figures S1 and S2).…”

Section: Identification Of Homozygous Mutations In Gp1ba Gpibb and supporting

confidence: 60%

“…Contrary to expectation, it was at the normal levels or partially reduced in carriers with p.Cys225Ser and p.Cys24Arg of the GPIbα and GPIX subunits, respectively. Such a discrepancy had already been observed previously, being the expression in obligate carriers with p.Cys225Ser (GPIbα) or p.Cys24Arg (GPIX) normal (or slightly reduced) 19,21 and close to 50% of controls in other cases. 7,28,29 We cannot explain these observations and any hypothesis would, at this time, be very speculative.…”

Section: Discussionmentioning

confidence: 71%

“…Of note, the only known mutation among this group was p.Cys24Arg, which was identified in a patient with mild clinical manifestations. 19 Having excluded a potential correlation with platelet count, the bleeding severity does not even associate with the expression of the GPIb/IX/V receptor. When genes GP1BA, GP1BB or GP9 are mutated, in the majority of cases the complex does not assemble in the endoplasmic reticulum and does not localize in the membrane.…”

Section: Discussionmentioning

confidence: 99%

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Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations

Savoia¹,

Pastore²,

Rocco³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. 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.Key words: Bernard-Soulier syndrome, macrothrombocytopenia, GP1BA, GP1BB and GP9 mutations. Citation: Savoia

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Section: Identification Of Homozygous Mutations In Gp1ba Gpibb and supporting

confidence: 60%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations

Savoia¹,

Pastore²,

Rocco³

et al. 2010

Haematologica

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“…However, naturally occurring mutations in BSS patients have been informative. Mutations affecting a leucine-rich domain of GPIX or its amino-and carboxy-terminal flanking regions all give rise to decreased GPIb/IX/V surface expression on platelets, suggesting that these regions are important to ensure the correct assembly and the stability of the complex [21]. The sequences flanking the LRM of GPIbb, GPIX, and GPIba are very similar, these regions showing conserved cysteine residues that form disulfide loops within the polypeptide, as observed in GPIba by crystallography [22].…”

Section: Discussionmentioning

confidence: 99%

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

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Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder due to quantitative or qualitative abnormalities in the platelet glycoprotein (GP) Ib/IX/V complex, the major von Willebrand factor receptor. The complex comprises four subunits, each encoded by a separate gene. Several mutations have been described for each of the subunits, except for GPV, as a cause of BSS. We describe here the genetic basis of the disorder in a child with BSS. Flow-cytometric analysis of the patient's platelets showed a markedly reduced surface expression of all three glycoproteins of the GPIb/IX/V complex. DNA sequencing analysis showed the patient to be a compound heterozygote for two mutations in the GPIX gene, a novel nine-nucleotide deletion starting at position 1952 of the gene that changes asparagine 86 for alanine and eliminates amino acids 87, 88, and 89 (arginine, threonine, and proline) and a previously reported point mutation that changes the codon asparagine (AAC) for serine (AGC) at residue 45. Her mother was heterozygous for the Asn45Ser mutation, and her father, for the nine-nucleotide deletion. Our findings suggest that the additive effects of both mutations in the GPIX gene are responsible for the BSS phenotype of the patient. Am.

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“…Loss of GATA1 site [81] 777C>T Arg17Cys [16] 790G>A Trp21stop [85] 945C>G Pro74Arg [17] 963delC Premature termination [86] 991A>G Tyr88Cys [18][19] 1050G>C Ala108Pro [18] 1096G>A Trp123stop S.K., et al, unpublished data GPIX Mutations 1717T>C Cys8Arg [87] 1757A>G Asp21Gly [88] 1811T>C Leu40Pro [89] 1826A>G Asn45Ser [88-90-91] 1856T>C Phe55Ser 1910G>A Cys73Tyr [22] 1982G>A Cys97Tyr [23] 2076G>A Trp127stop [14][15][16][17][18][19][20][21][22][23][24] *Nucleotide numbering for GPIbα, GPIbβ_, and GPIX is according to GenBank accession numbers M22403, U07983, and M80478, respectively. Table 6:-Proposed definitions of disease [30] Primary idiopathic thrombocytopenic  It is an autoimmune disorder characterized by isolated thrombocytopenia (peripheral blood platelet count <100 x 109/L) in the absence of other causes that may be associated with thrombocytopenia.…”

Section: C>gmentioning

confidence: 99%

A Case Report of Bernard-Soulier Syndrome in Differential Diagnosis of Immune Thrombocytopenic Purpura.

Wasfi¹,

ijar²

2018

IJAR

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Identification of a new mutation in platelet glycoprotein IX (GPIX) in a patient with Bernard–Soulier syndrome

Cited by 27 publications

References 8 publications

Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations

Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations

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

A Case Report of Bernard-Soulier Syndrome in Differential Diagnosis of Immune Thrombocytopenic Purpura.

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