Bernard-Soulier syndrome - GP1BA, GP1BB y GP9 genes

The Bernard-Soulier syndrome (BSS), also called hemorrhagic thrombocytic dystrophy, is a coagulation disorder that affects the megakaryocytic or platelet series and is characterized by a hemorrhagic syndrome with a decrease in the number of platelets that show a large size. This syndrome and other platelet alterations share similar clinical characteristics, including mucosal hemorrhages, purpuric syndrome, epistaxis, and menorrhagia. In this syndrome, the bleeding time is usually prolonged since there is no platelet aggregation in response to ristocetin or addition of von Willebrand factor (vWF). Thrombocytopenia may be present or absent.

The Bernard-Soulier syndrome may be due to mutations in one of the GP1BA (glycoprotein Ib platelet alpha subunit), GP1BB (glycoprotein Ib platelet beta subunit) or GP9 (glycoprotein IX platelet) genes. The proteins encoded from these genes are subunits of the GP complex complex Ib-IX-V. This complex is found on the surface of platelets and plays an important role in blood coagulation. The GP Ib-IX-V complex can bind to the von Willebrand factor, which is found on the inner surface of blood vessels, particularly when there is a lesion. The binding of the GP Ib-IX-V complex to vWF facilitates the initial adhesion of platelets to the vascular subendothelium after vascular injury.                        

The GP1BA gene (glycoprotein Ib platelet alpha subunit), located on the short arm of chromosome 17 (17p13.2), encodes the synthesis of glycoprotein Ib (GP Ib), which is a surface glycoprotein of the platelet membrane composed of a heterodimer, linked by disulfide bonds. The Gp Ib protein acts as a receptor for the vWF factor. The complete receptor complex includes a non-covalent association of the alpha and beta subunits with platelet glycoprotein IX and platelet glycoprotein V. The binding of the GP Ib-IX-V complex for vWF facilitates the initial adhesion of platelets to the vascular subendothelium after vascular injury, and it is also the signaling initiation factor inside the platelets for its activation, thrombosis and hemostasis. This gene encodes the alpha subunit. The coding region of this gene is known to contain a tandem repeat variable polymorph domain (VNTR) that is associated with the susceptibility to anterior non-arteritic ischemic optic neuropathy. This membrane protein participates in the formation of platelet plugs by binding to the A1 domain of vWF, which is already bound to the subendothelium. At least 54 mutations in the GP1BA gene have been described in people with Bernard-Soulier syndrome. Some of these mutations consist of nonsense mutations (20), regulatory mutations (1), small deletions (9), major deletions (2), small insertions (3) and repetition variations (1). Some of these mutations result in the synthesis of an altered Gp Ibα subunit that probably breaks down too soon or that cannot reach the surface of the platelets. The absence of this subunit on the surface of the platelets inhibits the formation of the GPIb-IX-V complex. Other mutations result in the synthesis of a subunit that can form complexes of GP Ib-IX-V, but cannot interact with vWF, which also affects the accumulation of platelets necessary for coagulation.

The GP1BB gene (glycoprotein Ib platelet beta subunit), located on the long arm of chromosome 22 (22q11.21), encodes the synthesis of the β subunit of platelet glycoprotein Ib (GPIb), a heterodimeric transmembrane protein consisting of an alpha chain of 140 kDa bound by disulfide bridges and a beta chain of 22 kDa. Mutations in the beta subunit of GPIb have been associated with Bernard-Soulier syndrome, velocardiofacial syndrome and giant platelet disorder. The protein is part of the GP Ib-IX-V system that constitutes the receptor for von Willebrand factor (vWF) and mediates the adhesion of platelets in the arterial circulation. The alpha chain GPIb provides the binding site of the vWF factor. Beta GPIb contributes to surface expression of the transmembrane receptor and participates in signaling through the phosphorylation of its intracellular domain. At least 32 mutations in the GP1BB gene related to the Bernard-Soulier syndrome have been identified. Some of these mutations consist of nonsense mutations (16), regulatory mutations (1), small deletions (3), major deletions (2) and small insertions (2). These mutations result in the synthesis of an altered GPIbβ subunit that probably breaks down too early or cannot reach the surface of platelets.

The GP9 gene (glycoprotein IX platelet), is found on the long arm of chromosome 3 (3q21.3) and encodes the synthesis of a small platelet surface membrane glycoprotein (GPIX). It forms a non-covalent 1-to-1 complex with glycoprotein Ib. The complete receptor complex includes the non-covalent association of alpha and beta subunits with the protein encoded by this gene and glycoprotein V. At least 28 mutations in the GP9 gene have been described as responsible for the development of Bernard-Soulier syndrome. Some of these mutations consist of nonsense mutations (16), small deletions (3), small insertions (1) and major insertions / duplications (1). These mutations cause the synthesis of an altered GPIX subunit that probably breaks down too soon or that cannot reach the surface of the platelets.

This disease can have an autosomal recessive or dominant inheritance pattern. Most cases of Bernard-Soulier syndrome are inherited in an autosomal recessive pattern, which means that both copies of the gene in each cell must have the mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease. Although most people with only one copy of the mutated gene do not show signs and symptoms of the disease, some have platelets that are slightly larger or have very mild bleeding abnormalities. Some rare cases of the syndrome due to mutations in GP1BA or GP1BB genes, are inherited with an autosomal dominant inheritance pattern, which means that a copy of the altered gene in each cell is sufficient for the disease to be expressed.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Bernard-Soulier syndrome, by means of the complete PCR amplification of the exons of the GP1BA, GP1BB y GP9 genes, respectively, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).