PMID- 10607701
OWN - NLM
STAT- MEDLINE
DCOM- 20000131
LR  - 20211203
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 95
IP  - 1
DP  - 2000 Jan 1
TI  - A naturally occurring mutation near the amino terminus of alphaIIb defines a new 
      region involved in ligand binding to alphaIIbbeta3.
PG  - 180-8
AB  - Decreased expression of functional alphaIIbbeta3 complexes on the platelet
      surface produces Glanzmann thrombasthenia. We have identified mutations of
      alphaIIb(P145) in 3 ethnically distinct families affected by Glanzmann
      thrombasthenia. Affected Mennonite and Dutch patients were homozygous and doubly 
      heterozygous, respectively, for a P(145)A substitution, whereas a Chinese patient
      was doubly heterozygous for a P(145)L substitution. The mutations affect
      expression levels of surface alphaIIbbeta3 receptors on their platelets, which
      was confirmed by co-transfection of alphaIIb(P145A) and beta3 cDNA constructs in 
      COS-1 cells. Each mutation also impaired the ability of alphaIIbbeta3 on affected
      platelets to interact with ligands. Moreover, when alphaIIb(P145A) and beta3 were
      stably coexpressed in Chinese hamster ovary cells, alphaIIbbeta3 was readily
      detected on the cell surface, but the cells were unable to adhere to immobilized 
      fibrinogen or to bind soluble fluorescein isothiocyanate-fibrinogen after
      alphaIIbbeta3 activation by the activating monoclonal antibody PT25-2.
      Nonetheless, incubating affected platelets with the peptide LSARLAF, which binds 
      to alphaIIb, induced PF4 secretion, indicating that the mutant alphaIIbbeta3
      retained the ability to mediate outside-in signaling. These studies indicate that
      mutations involving alphaIIb(P145 )impair surface expression of alphaIIbbeta3 and
      that the alphaIIb(P145A) mutation abrogates ligand binding to the activated
      integrin. A comparative analysis of other alphaIIb mutations with a similar
      phenotype suggests that these mutations may cluster into a single region on the
      surface of the alphaIIb and may define a domain influencing ligand binding.
      (Blood. 2000;95:180188)
FAU - Basani, R B
AU  - Basani RB
AD  - Departments of Pediatrics and Medicine, University of Pennsylvania School of
      Medicine, Philadelphia, PA, USA.
FAU - French, D L
AU  - French DL
FAU - Vilaire, G
AU  - Vilaire G
FAU - Brown, D L
AU  - Brown DL
FAU - Chen, F
AU  - Chen F
FAU - Coller, B S
AU  - Coller BS
FAU - Derrick, J M
AU  - Derrick JM
FAU - Gartner, T K
AU  - Gartner TK
FAU - Bennett, J S
AU  - Bennett JS
FAU - Poncz, M
AU  - Poncz M
LA  - eng
GR  - HL 19278/HL/NHLBI NIH HHS/United States
GR  - HL 40387/HL/NHLBI NIH HHS/United States
GR  - HL56369/HL/NHLBI NIH HHS/United States
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Ligands)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Platelet Glycoprotein GPIIb-IIIa Complex)
RN  - 0 (Recombinant Proteins)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Amino Acid Substitution
MH  - Animals
MH  - Binding Sites
MH  - Blood Platelets/physiology
MH  - CHO Cells
MH  - COS Cells
MH  - Child, Preschool
MH  - China/ethnology
MH  - Christianity
MH  - Cricetinae
MH  - Ethnicity/genetics
MH  - Female
MH  - Heterozygote
MH  - Humans
MH  - Ligands
MH  - Macromolecular Substances
MH  - Male
MH  - Models, Molecular
MH  - Netherlands/ethnology
MH  - Pennsylvania
MH  - Platelet Glycoprotein GPIIb-IIIa Complex/chemistry/*genetics/metabolism
MH  - *Point Mutation
MH  - Protein Structure, Secondary
MH  - Recombinant Proteins/metabolism
MH  - Thrombasthenia/*genetics
MH  - Transfection
MH  - Whites/genetics
EDAT- 1999/12/23 00:00
MHDA- 1999/12/23 00:01
CRDT- 1999/12/23 00:00
PHST- 1999/12/23 00:00 [pubmed]
PHST- 1999/12/23 00:01 [medline]
PHST- 1999/12/23 00:00 [entrez]
AID - S0006-4971(20)36604-0 [pii]
PST - ppublish
SO  - Blood. 2000 Jan 1;95(1):180-8.