Point mutation in a Leucine-rich repeat of platelet glycoprotein Ibα resulting in the Bernard-Soulier syndrome

Jerry Ware, Susan R. Russell, Patrizia Marchese, Mitsuru Murata, Mario Mazzucato, Luigi De Marco, Zaverio M. Ruggeri

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Leucine-rich repeats are a conserved structural motif, of yet undefined significance, found in a group of proteins from different species. Among these are the four components of the human platelet glycoprotein Ib-IX-V complex, a membrane receptor that performs an essential role in the thrombogenic function of platelets by interacting with the adhesive protein, von Willebrand factor. We have found that a single amino acid substitution (Ala156 → Val) within one of the six leucine-rich repeats in the α-subunit of glycoprotein Ib results in a variant form of the congenital bleeding disorder, Bernard-Soulier syndrome, characterized by giant dysfunctional platelets. Genetic studies of the propositus and his family members were complemented by immunological and functional analysis of expressed recombinant GP Ibα fragments to demonstrate that the observed mutation is the cause of defective von Willebrand factor binding. These studies define the molecular basis of the Bernard-Soulier syndrome within this family and demonstrate that structural integrity of a leucine-rich repeat is necessary for normal function of the glycoprotein Ib-IX-V receptor complex and, possibly, for normal platelet morphology.

Original languageEnglish
Pages (from-to)1213-1220
Number of pages8
JournalJournal of Clinical Investigation
Volume92
Issue number3
Publication statusPublished - 1993 Sep
Externally publishedYes

Fingerprint

Bernard-Soulier Syndrome
Platelet Glycoprotein GPIb-IX Complex
Platelet Membrane Glycoproteins
Point Mutation
Leucine
Blood Platelets
von Willebrand Factor
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Amino Acid Substitution
Adhesives
Proteins
Hemorrhage
Mutation
Membranes

Keywords

  • Bleeding disorder
  • Giant platelets
  • Platelet adhesion
  • Thrombosis
  • Von Willebrand factor

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ware, J., Russell, S. R., Marchese, P., Murata, M., Mazzucato, M., De Marco, L., & Ruggeri, Z. M. (1993). Point mutation in a Leucine-rich repeat of platelet glycoprotein Ibα resulting in the Bernard-Soulier syndrome. Journal of Clinical Investigation, 92(3), 1213-1220.

Point mutation in a Leucine-rich repeat of platelet glycoprotein Ibα resulting in the Bernard-Soulier syndrome. / Ware, Jerry; Russell, Susan R.; Marchese, Patrizia; Murata, Mitsuru; Mazzucato, Mario; De Marco, Luigi; Ruggeri, Zaverio M.

In: Journal of Clinical Investigation, Vol. 92, No. 3, 09.1993, p. 1213-1220.

Research output: Contribution to journalArticle

Ware, J, Russell, SR, Marchese, P, Murata, M, Mazzucato, M, De Marco, L & Ruggeri, ZM 1993, 'Point mutation in a Leucine-rich repeat of platelet glycoprotein Ibα resulting in the Bernard-Soulier syndrome', Journal of Clinical Investigation, vol. 92, no. 3, pp. 1213-1220.
Ware, Jerry ; Russell, Susan R. ; Marchese, Patrizia ; Murata, Mitsuru ; Mazzucato, Mario ; De Marco, Luigi ; Ruggeri, Zaverio M. / Point mutation in a Leucine-rich repeat of platelet glycoprotein Ibα resulting in the Bernard-Soulier syndrome. In: Journal of Clinical Investigation. 1993 ; Vol. 92, No. 3. pp. 1213-1220.
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