A novel homozygous 8-base pair deletion mutation in the glycoprotein Ibα gene in a patient with Bernard–Soulier syndrome

• DOI: 10.1097/mbc.0b013e32832b27fa
• Publication Date: 2009-08-13T18:49:57Z
• Authors: Chihaya Imai; Shinji Kunishima; Takayuki Takachi; Haruko Iwabuchi; Tae Nemoto; Masaru Imamura; Makoto Uchiyama
• Keywords: 0301 basic medicine; Membrane Glycoproteins; DNA Mutational Analysis; Homozygote; Molecular Sequence Data; Bernard-Soulier Syndrome; Infant; Minisatellite Repeats; Polymorphism, Single Nucleotide; 3. Good health; 03 medical and health sciences; Epistaxis; Platelet Glycoprotein GPIb-IX Complex; Codon, Nonsense; Diseases in Twins; Humans; Female; Amino Acid Sequence; Frameshift Mutation; Sequence Deletion

We present a patient with Bernard-Soulier syndrome harboring a novel mutation. Flow cytometric analysis showed that the glycoprotein (GP) Ib/IX complex was absent from the platelet surface. By immunoblotting, GPIbalpha, GPIbbeta and GPIX were not detected in the platelet lysates. Glycocalicin, the soluble GPIbalpha fragment, was also absent in the plasma. Genetic analysis revealed a novel homozygous 8-base pair deletion in the GPIbalpha gene, 1136_1143delTTCACATG, which was predicted to cause a frame shift and the addition of 13 altered amino acids followed by premature termination. No mutation was found in the coding sequence of the GPIbbeta or GPIX genes. We demonstrated that the novel deletion mutation resulted in complete defectiveness of the GPIbalpha protein and null expression of the entire GPIb/IX complex, and was responsible for the Bernard-Soulier syndrome phenotype in this patient. Although the presence of a truncated GPIbalpha protein has been often documented, complete absence of the protein has been scarcely reported in Bernard-Soulier syndrome patients with a GPIbalpha mutation causing a premature stop codon. An underlying molecular mechanism to explain how the synthesis of a truncated protein is inhibited in selected cases remains to be elucidated.