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The genetic defect in two well-studied cases of Bernard-Soulier syndrome: a
point mutation in the fifth leucine-rich repeat of platelet glycoprotein Ib
alpha
C Li, SE Martin and GJ Roth
Hematology Section, Seattle Veterans Administration Medical Center, WA
98108, USA.
Bernard-Soulier syndrome (B-Ss) is a rare congenital bleeding disorder
caused by abnormal giant platelets, thrombocytopenia, and defective
glycoprotein (GP) Ib-V-IX, the adhesion receptor for von Willebrand factor
(vWF). This report describes the molecular defect in two related
individuals with well-established B-Ss whose platelets exhibit decreased
GPIb-IX and normal GPV on their surfaces. The GPIb-V-IX genes of the two
patients were analyzed by Southern blotting, hetero-duplex analysis, and
polymerase chain reaction (PCR) amplification/sequencing. A point mutation
was found in codon 129 of the GPIb alpha gene that results in the
substitution of proline for leucine in the first position of the fifth
leucine-rich glycoprotein repeat of the mature gene product. The mutation
(CTC: leucine, wild-type to CCC: proline, mutant) eliminates a Sac I
restriction site, facilitating analysis of the mutation in the propositi
(both homozygotes), unaffected family members (8 heterozygotes and 8
wild-type), and 58 normal controls (116 wild-type alleles). The status of
the genomes was confirmed by the sequencing of platelet cDNA. The mutation
does not affect transcription of the Ib-IX genes, as estimated by PCR and
Northern blot analysis, but it does inhibit surface expression of the
receptor as assessed by transient transfection of mutant and wild-type GPIb
alpha genes into mouse Ib beta-IX L cells. Many of the cells (43%)
transfected with the normal gene express surface GPIb alpha, whereas
untransfected cells and those transfected with the mutant gene lack surface
GPIb alpha entirely. Patient platelets were tested both for vWF binding in
the presence of ristocetin and for surface GPIb-IX expression. In these
instances, despite their inability to agglutinate with ristocetin and vWF,
patient platelets exhibit about 40% of normal vWF binding and 40% of normal
Ib-IX surface antigens. The results suggest that the described mutation
(GPIb alpha: Leu129 -> Pro) affects the conformation of the GPIb-V-IX
receptor, alters its availability on platelet surfaces, and causes the
observed Bernard-Soulier phenotype.
Volume 86,
Issue 10,
pp. 3805-3814,
11/15/1995
Copyright © 1995 by The American Society of Hematology
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