title: Compound heterozygosity of the GPIbalpha gene associated with Bernard-Soulier syndrome.
abstract: We report the molecular genetic analysis of the Bernard-Soulier syndrome (BSS) phenotype in two related patients showing absence of glycoprotein (GP) Ibalpha and detectable amounts of GPIX on the platelet surface, and a truncated form of GPIbalpha in solubilized platelets and plasma. They both were compound heterozygotes for the GPIbalpha gene: a maternal allele with a T insertion at position 1418 causing a translational frameshift and premature polypeptide termination, and a paternal allele with a T715A substitution chan-ino Cys209 to Ser. Heterozygotes for either one of these mutations were asymptomatic. Transient transfection of cells coexpressing GPIbbeta and GPIX failed to detect surface expression of the GPIbalpha mutants. Cells transfected with [1418insT]GPIbalpha-cDNA showed a truncated protein of the predicted size in both cell lysate and conditioned medium, indicating the inability of the mutant protein to anchor the plasma membrane. In contrast. transfection of [T715A]GPIbalpha-cDNA yield a mutated protein barely detectable in the cell lysate and absent in the medium, indicating that the loss of Cys209 renders GPIbalpha more vulnerable to proteolysis and unable to undergo the normal secretory pathway. Our findings indicate that the additive effects of both mutations are responsible for the BSS phenotype of the patients.
authors.affiliation: Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain. cgmanchon@cib.csic.es
authors.forename: C
authors.initials: C
authors.lastname: González-Manchón
authors.forename: S
authors.initials: S
authors.lastname: Larrucea
authors.forename: A L
authors.initials: AL
authors.lastname: Pastor
authors.forename: N
authors.initials: N
authors.lastname: Butta
authors.forename: E G
authors.initials: EG
authors.lastname: Arias-Salgado
authors.forename: M S
authors.initials: MS
authors.lastname: Ayuso
authors.forename: R
authors.initials: R
authors.lastname: Parrilla
mesh_terms: D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001606:Bernard-Soulier Syndrome / Q000235:genetics*; D001792:Blood Platelets / Q000737:chemistry; D016466:CHO Cells; D018389:Codon, Nonsense; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D016254:Mutagenesis, Insertional; D020125:Mutation, Missense; D010641:Phenotype; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D014162:Transfection
chemical_list: D018389:Codon, Nonsense; D018076:DNA, Complementary; D019038:Platelet Glycoprotein GPIb-IX Complex