Novel mutations of integrin αIIb and β3 genes in Turkish children with Glanzmann's thrombasthenia.
Glanzmann's thrombasthenia (GT) is an inherited disorder of platelet aggregation, characterized by qualitative and quantitative defect on platelet αIIbβ3 integrin (GpIIb/IIIa), resulting in lifelong bleeding tendency due to defective platelet plug formation. The αIIb gene (ITGA2B) and β3 gene (ITGB3) are closely located at chromosome 17q21.31-32. ITGA2B consist of 30 exons and encoding α chain, whereas ITGB3 has 15 exons and encoding β chain. Until now, according to the Human Gene Mutation Database (HGMD), 138 mutations at ITGA2B gene and 101 mutations at ITGB3 gene have been identified. We aimed to determine whether there was any mutation in the ITGA2B and ITGB3 genes, and a correlation between clinical phenotype and genotype in Turkish GT patients. We examined 20 patients with GT followed at the Department of Pediatric Hematology, Meram Faculty of Medicine, for Clinical and Laboratory Findings and Molecular Genetic Analysis. Peripheral blood was collected from patients, and a written informed consent for genetic analysis was obtained from parents. DNA was isolated from by proteinase K and phenol/chloroform extraction. ITGA2B and ITGB3 genes were screened by polymerase chain reaction. There were 12 females and 8 males with a median age of 15.25 years. Major clinical presentations of these patients were mucocutaneous bleedings. The most common bleeding type was epistaxis (85%). Life-threatening bleedings were seen in five patients. Seven (35%) patients showed various mutations in the ITGA2B or ITGB3 genes. We detected four novel mutations in three different regions and two mutations defined previously within the ITGA2B gene. These changes are at exon 4; c.570 T > G alteration, at exon 13 c.1277 T > A, c.1291 T > G alterations, at exon 19 c.1921A > G alterations. And from the start point of exon 14, behind 107 bases, we detected a heterozygous alteration at Thymine to Guanine. According to PolyPhen Database Program and NCBI Multiple Alignment Tool Database, four transitions are conserved at evolutionary process, so we can say that these transitions are novel mutations. c. 468T > G alteration at exon 4 and c. 1378 T > A alteration at exon 13 were reported to HGMD previously. Screening the exons of the ITGB3 gene from the same patient groups, we reported a novel missense mutation at exon 5, at nucleotide 680. No correlation was found between clinical phenotype and genotype. These mutations were described for the first time in Turkish population, and all novel mutations are not defined previously. Furthermore, collaborative studies are needed for the population point of view.
a Meram Faculty of Medicine, Department of Pediatric Hematology, Necmettin Erbakan University , Konya , Turkey .
Huseyin
H
Tokgoz
b Okan University, Faculty of Medicine , Department of Medical Biology , İstanbul , Turkey , and.
Didem
D
Torun Ozkan
a Meram Faculty of Medicine, Department of Pediatric Hematology, Necmettin Erbakan University , Konya , Turkey .
Umran
U
Caliskan
c TOBB Economy and Technology Hospital , Department of Pediatrics , Ankara , Turkey.
Nejat
N
Akar
D000293:Adolescent; D000328:Adult; D001792:Blood Platelets / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D010974:Platelet Aggregation; D010976:Platelet Count; D010979:Platelet Function Tests; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics*; D013915:Thrombasthenia / Q000175:diagnosis / Q000235:genetics*; D014421:Turkey; D055815:Young Adult
C061248:ITGB3 protein, human; D039661:Integrin beta3; D040201:Platelet Membrane Glycoprotein IIb
Glanzmann thrombasthenia; mutation analysis; polymorphism