Characterisation of patients with Glanzmann thrombasthenia and identification of 17 novel mutations.
Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder characterised by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex, also called integrin αIIbβ3. αIIbβ3 is well known as a platelet fibrinogen receptor and mediates platelet aggregation, firm adhesion, and spreading. This study describes the molecular genetic analyses of 19 patients with GT who were diagnosed on the basis of clinical parameters and platelet analyses. The patients' bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, gastrointestinal bleeding, and menorrhagia. Homozygous or compound heterozygous mutations in ITGA2B or ITGB3 were identified as causing GT by sequencing of genomic DNA. All exons including exon/intron boundaries of both genes were analysed. In a patient with an intronic mutation, splicing of mRNA was analysed using reverse transcriptase (RT)-PCR of platelet-derived RNA. In short, 16 of 19 patients revealed 27 different mutations (ITGA2B: n=17, ITGB3: n=10). Seventeen of these mutations have not been published to date. Mutations in ITGA2B or ITGB3 were identified as causing GT in 16 patients. We detected a total of 27 mutations in ITGA2B and ITGB3 including 17 novel missense, nonsense, frameshift and splice site mutations. In addition, three patients revealed no molecular genetic anomalies in ITGA2B or ITGB3 that could explain the suspected diagnosis of GT. We assume that these patients may harbour defects in a regulatory element affecting the transcription of these genes, or other proteins may exist that are important for activating the αIIbβ3 complex that may be affected.
Kirstin
K
Sandrock-Lang
Johannes
J
Oldenburg
Verena
V
Wiegering
Susan
S
Halimeh
Sentot
S
Santoso
Karin
K
Kurnik
Lars
L
Fischer
Dimitiros A
DA
Tsakiris
Michael
M
Sigl-Kraetzig
Brigitte
B
Brand
Martina
M
Bührlen
Katharina
K
Kraetzer
Niklas
N
Deeg
Martin
M
Hund
Eileen
E
Busse
Anja
A
Kahle
Prof. Dr. Barbara Zieger, University Medical Center Freiburg, Department of Pediatrics and Adolescent Medicine, Mathildenstr. 1, 79106 Freiburg, Germany, Tel.: +49 761 27043000, Fax: +49 761 27045820, E-mail: barbara.zieger@uniklinik-freiburg.de.
Barbara
B
Zieger
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D039421:Integrin alpha2 / Q000235:genetics*; D039661:Integrin beta3 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010974:Platelet Aggregation; D010979:Platelet Function Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013915:Thrombasthenia / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
D005819:Genetic Markers; C056564:ITGA2B protein, human; C061248:ITGB3 protein, human; D039421:Integrin alpha2; D039661:Integrin beta3
Glanzmann thrombasthenia; glycoprotein αIIbβ3; platelet function defect