title: Variant Bernard-Soulier syndrome due to homozygous Asn45Ser mutation in the platelet glycoprotein (GP) IX in seven patients of five unrelated Finnish families.
abstract: Bernard-Soulier syndrome (BSS), a rare bleeding disorder with macrothrombocytopenia, is caused by a defect of the platelet glycoprotein (GP) Ib/IX/V complex. Here we report a variant form of BSS in eleven patients of five unrelated families who originate from a particular area of Finland. The differential diagnosis from idiopathic thrombocytopenic purpura was difficult. Bleeding symptoms were epistaxis and haematomas debuting in childhood, but no spontaneous, severe bleeding episodes were reported. The platelet count varied from 43 to 81x10(9)/l. Screening the entire GP Ibalpha, GP Ibbeta, GP IX and GP V genes revealed a recurrent homozygous Asn45Ser mutation in GP IX in all probands. Flow cytometry showed markedly reduced expression of GP Ib (<10%), and only moderately reduced expression of GP IX (24-36%) and GP V (38-49%). The expression of subunits seemed to vary independently from the normal polymorphisms. Heterozygotes did not differ significantly from controls by their GP Ib/IX/V expression. Since the Asn45Ser mutation has also been reported in three other kindreds of northern and central European origin, this study reveals that instead of being a mutation hot spot, it may be ancient and scattered in Europe. Moderate, chronic thrombocytopenia should be carefully studied to diagnose variant BSS correctly from treatment resistant idiopathic thrombocytopenia.
authors.affiliation: Finnish Red Cross Blood Transfusion Service, Helsinki.
authors.forename: S
authors.initials: S
authors.lastname: Koskela
authors.forename: K
authors.initials: K
authors.lastname: Javela
authors.forename: J
authors.initials: J
authors.lastname: Jouppila
authors.forename: E
authors.initials: E
authors.lastname: Juvonen
authors.forename: O
authors.initials: O
authors.lastname: Nyblom
authors.forename: J
authors.initials: J
authors.lastname: Partanen
authors.forename: R
authors.initials: R
authors.lastname: Kekomäki
mesh_terms: D019943:Amino Acid Substitution; D001216:Asparagine; D001606:Bernard-Soulier Syndrome / Q000097:blood / Q000235:genetics*; D005260:Female; D005387:Finland; D014644:Genetic Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics*; D017354:Point Mutation; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D012694:Serine
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex; D012694:Serine; D001216:Asparagine