Trp207Gly in platelet glycoprotein Ibalpha is a novel mutation that disrupts the connection between the leucine-rich repeat domain and the disulfide loop structure and causes Bernard-Soulier syndrome.
BACKGROUND
Bernard-Soulier syndrome (BSS) is a severe inherited bleeding disorder that is caused by a defect in glycoprotein (GP)Ib-IX-V complex, the platelet membrane receptor for von Willebrand factor.


METHODS
The diagnosis of BSS was made in two members of a Bukharian Jewish family who had life-long thrombocytopenia associated with mucocutaneous bleeding manifestations.


RESULTS
Flow cytometry and Western blot analyses showed only trace amounts of GPIb and GPIX on the patients' platelets. Sequence analysis of the GPIbalpha gene revealed a homozygous T > G transversion at nucleotide 709 predicting Trp207Gly substitution in the mature protein. Introduction of the mutation into a mammalian expression construct abolished the surface expression of GPIbalpha in transfected baby hamster kidney cells. The crystal structure of the N-terminus of GPIbalpha (PDB: 1SQ0) indicates that Trp207 is completely buried and located in a disulfide loop structure that interacts with the leucine-rich repeat (LRR) domain.


CONCLUSIONS
A novel mutation, Trp207Gly, causes BSS and predicts disruption of the interaction between a disulfide loop and the LRR domain that is essential for the integrity of GPIbalpha structure.
Rosenberg
N
N
Amalia Biron Research Institute of Thrombosis and Hemostasis, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Lalezari
S
S
Landau
M
M
Shenkman
B
B
Seligsohn
U
U
Izraeli
S
S
D000293:Adolescent; D020816:Amino Acid Motifs; D001606:Bernard-Soulier Syndrome / Q000209:etiology / Q000235:genetics*; D001792:Blood Platelets / Q000737:chemistry; D002648:Child; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D005260:Female; D006470:Hemorrhage; D006801:Humans; D007585:Jews; D007930:Leucine; D020125:Mutation, Missense; D010375:Pedigree; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000032:analysis / Q000737:chemistry* / Q000235:genetics*; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012091:Repetitive Sequences, Nucleic Acid; D013921:Thrombocytopenia
D019038:Platelet Glycoprotein GPIb-IX Complex; C023592:glycocalicin; D007930:Leucine