title: Novel Bernard-Soulier syndrome variants caused by compound heterozygous mutations (case I) or a cytoplasmic tail truncation (case II) of GPIbα.
abstract: A defective platelet glycoprotein (GP) Ib/IX/V complex [von Willebrand factor (VWF) receptor] results in Bernard-Soulier syndrome (BSS), which is characterized by macrothrombocytopenia and impaired ristocetin- and thrombin-induced platelet aggregation. We found 2 independent BSS-variant families: Case I [compound heterozygous mutations, p.Glu331X and a frame shift by a deletion at c.1444delA of GPIbα (GP1BA) terminating at a premature stop codon (p.Thr452ProfsX58)], and case II [homozygous nonsense mutation at c.1723C>T, p.Gln545X]. Case I platelets expressed no GPIbα, resulting in absence of ristocetin-induced platelet aggregation (RIPA) and 50% reduction in thrombin-induced aggregation with no shape change. The mother's platelets had 50% the expression level of A-type GPIbα (4-repeated VNTR: variable number of tandem repeats, p.[Thr145Met; Ser399_Pro411[4]]); the father's platelets had the same expression level of C-type GPIbα (2-repeated VNTR, p.Ser399_Pro411dup) as the mother's platelets. The mother's RIPA was significantly higher than the father's. Thrombin-induced aggregation was normal in both parents. Case II platelets expressed a GPIbα with an abnormal cytoplasmic tail, p.Gln545X-truncated GPIbα, which complexed with GPIX and GPV on the cell surface; its expression level of the complex was normal. Case II platelets had reversible RIPA, with no ATP release, and weak thrombin-induced aggregation without shape change. These results suggest that a signaling process through the GPIbα cytoplasmic tail required for full platelet activation is defective in BSS variant case II and a length polymorphism of GPIbα is associated with a modified level of RIPA heterozygous BSS case I.
authors: Department of Biochemistry, School of Pharmaceutical Sciences, Ohu University, Koriyama, Fukushima 963-8611, Japan. n-yamamoto@pha.ohu-u.ac.jp
authors: Naomasa
authors: N
authors: Yamamoto
authors: Noriko
authors: N
authors: Akamatsu
authors: Hitoshi
authors: H
authors: Sakuraba
authors: Kazuhiko
authors: K
authors: Matsuno
authors: Ryota
authors: R
authors: Hosoya
authors: Haruo
authors: H
authors: Nogami
authors: Kohji
authors: K
authors: Kasahara
authors: Susumu
authors: S
authors: Mitsuyama
authors: Morio
authors: M
authors: Arai
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001606:Bernard-Soulier Syndrome / Q000097:blood* / Q000235:genetics*; D001792:Blood Platelets / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics*; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex