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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4712-4720
Truncation of Glycoprotein (GP) IIIa ( 616-762) Prevents
Complex Formation With GPIIb: Novel Mutation in Exon 11 of
GPIIIa Associated With Thrombasthenia
Milagros Ferrer,
Jianming Tao,
Gema Iruín,
Matilde Sánchez-Ayuso,
José González-Rodríguez,
Roberto Parrilla, and
Consuelo González-Manchón
From the Department of Pathophysiology and Human Molecular Genetics,
Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; the
Instituto Rocasolano, Madrid (CSIC), Madrid, Spain; and the Department
of Haematology, Hospital de Cruces, Baracaldo, Bilbao, Spain.
This work reports the molecular genetic study of a patient who
suffered from Glanzmann thrombasthenia (GT). Structural analysis of the
glycoprotein (GP) IIb and GPIIIa genes showed the presence of a
homozygous G1846 T transversion in exon 11 of
GPIIIa that changes Glu616Stop. Cytometric and
immunochemical analysis indicated that platelet GPIIb-IIIa was absent
in the proband but present at normal levels in the heterozygous
relatives. The following observations indicate that this mutation is
responsible for the thrombasthenic phenotype of the proband. (1) We
failed to detect mutations other than [T1846]GPIIIa in
the coding region of both GPIIb and GPIIIa genes. (2) The
G1846T mutation was observed in either parent and
a brother of the proband, but none of 100 unrelated individuals carried
this defect. (3) Pulse-chase and immunoprecipitation analysis of
GPIIb-IIIa complexes in cells transiently cotransfected with cDNAs
encoding normal GPIIb and [T1846]GPIIIa showed neither
maturation of GPIIb nor complex formation and surface exposure of
GPIIb- GPIIIa. These observations indicate that the sequence from
Glu616 to Thr762 in GPIIIa is essential for
heterodimerization with GPIIb. Polymerase chain reaction-based analysis
demonstrated the presence of normal levels of full-length GPIIIa-mRNA
in the proband and in heterozygous relatives. In addition, a shortened
transcript, with a 324-nucleotide deletion, resulting from in-frame
skipping of exons 10 and 11, was detectable upon reamplification of the
DNA. Thus, unlike other nonsense mutations, [T1846]GPIIIa
does not lead to abnormal processing or reduction in the number of
transcripts with the termination codon.
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