A novel homozygous 8-base pair deletion mutation in the glycoprotein Ibα gene in a patient with Bernard–Soulier syndrome

Abstract

We present a patient with Bernard-Soulier syndrome harboring a novel mutation. Flow cytometric analysis showed that the glycoprotein (GP) Ib/IX complex was absent from the platelet surface. By immunoblotting, GPIbalpha, GPIbbeta and GPIX were not detected in the platelet lysates. Glycocalicin, the soluble GPIbalpha fragment, was also absent in the plasma. Genetic analysis revealed a novel homozygous 8-base pair deletion in the GPIbalpha gene, 1136_1143delTTCACATG, which was predicted to cause a frame shift and the addition of 13 altered amino acids followed by premature termination. No mutation was found in the coding sequence of the GPIbbeta or GPIX genes. We demonstrated that the novel deletion mutation resulted in complete defectiveness of the GPIbalpha protein and null expression of the entire GPIb/IX complex, and was responsible for the Bernard-Soulier syndrome phenotype in this patient. Although the presence of a truncated GPIbalpha protein has been often documented, complete absence of the protein has been scarcely reported in Bernard-Soulier syndrome patients with a GPIbalpha mutation causing a premature stop codon. An underlying molecular mechanism to explain how the synthesis of a truncated protein is inhibited in selected cases remains to be elucidated.

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

“…[8][9][10][11][12][13] Most of the mutations prevent the coordinated association of the complex, resulting in very low expression of GPIb/IX/V itself on the platelet membrane. 6 In other cases, the complex is normal or slightly decreased but unable to bind the von Willebrand factor.…”

A Novel Homozygous c.800C>G Substitution in <b><i>GP1BA</i></b> Exon 2 in a Kuwaiti Family with Bernard-Soulier Syndrome

“…a mutation in GPIX resulting in an Asn45Ser substitution has been reported in several Caucasian families in different countries [12,13,14]. In some cases, more than one mutation has been described [11,15,16], and while most mutations affect the extracellular portion of the GPIb/IX complex, mutations in the transmembrane portion [17,18] and signal sequence of GPIX [19] have also been reported. Generally, these mutations are autosomal recessive and obligate heterozygote carriers of BSS mutations are usually clinically unaffected, have normal or slightly reduced levels of GPIb/IX and a platelet volume within the upper regions of the normal range; however, some mutations, e.g.…”

“…In most European BSS patients the disease is caused by missense mutations leading to a single amino acid substitution in GPIX . Deletion defects are less commonly observed [10,11]. Most mutations are unique to a single individual or family, although there are some exceptions, e.g.…”