title: Molecular pathogenesis of Bernard-Soulier syndrome.
abstract: Bernard-Soulier syndrome (BSS), a hereditary qualitative platelet disorder, is now proved to be caused by a qualitative or quantitative abnormality of the platelet glycoprotein (GP) Ib/IX/V complex. We investigated the genetic background of two Japanese females with BSS and identified the molecular defects underlying this disease. The first case was a single base pair deletion within seven adenine repeats at position 4464-4470 (EMBL, no. M22403) of the GPIbalpha gene resulting in a frameshift and a premature stop codon. The second case was a single T-->C substitution at nucleotide 1856 (EMBL, no. M80478) of the GPIX gene resulting in Phe55(TTT)-->Ser(TCT) substitution. The latter case is of interest in considering the pathogenesis of BSS, because all four GPs consisting of the GPIb/IX/V complex have the same structural unit called leucine-rich repeat (LRR). Because this mutation is located within the LRR of the GPIX polypeptide, Phe55-->Ser substitution may result in an alteration of the LRR that leads to impaired surface expression of the GPIb/IX/V complex. To clarify the effect of this mutation on surface expression of the GPIb/IX complex, we performed transfection studies with a plasmid having this mutation. Mutant GPIX could not increase surface expression of the GPIb/IX complex, thus demonstrating an important role of the LRR of the GPIX polypeptide during biosynthesis.
authors.affiliation: Third Department of Internal Medicine, Yamagata University School of Medicine, Japan. thayashi@med.id.yamagata-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D020029:Base Pairing; D001606:Bernard-Soulier Syndrome / Q000235:genetics*; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D016415:Sequence Alignment; D017384:Sequence Deletion; D013728:Terminator Regions, Genetic / Q000235:genetics
chemical_list: D003062:Codon; D046911:Macromolecular Substances; D019038:Platelet Glycoprotein GPIb-IX Complex