A Novel Mutation (Q694X) in the ITGB3 Gene Causing Glanzmann’s Thrombasthenia from the Sultanate of Oman
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عرض / فتح
التاريخ
2008-11-16المؤلف
Albalushi, TalalAlZadjali, Shoaib
AlHaddabi, Hamood
Dennison, J. David
Alkindi, Salam
Muralitharan, Shanmugaonkar
Arinami, Tadao
Pathare, Anil
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البيانات الوصفية
عرض كامل للتسجيلةالملخص
Background: Glanzmann Thrombasthenia (GT) results from mutations in the genes ITGA2B and ITGB3, located on chromosome 17q21–23 which encodes the platelet glycoprotein αIIbβ3 complex, namely GPIIb (αIIb) and GPIIIa (β3), the fibrinogen receptors on platelets, which play an important role in platelet aggregation. Patients with GT can require frequent hospitalization and can be a burden on the nation’s health resources. The possibility that GT could be cured by gene replacement therapy makes it essential to study the molecular basis of the GT patients in a particular family or kindred.
Objectives: Our aim was to identify the underlying mutations responsible for GT in Omani patients in order to establish a strategy for genetic counseling and carrier detection to prevent the occurrence of the homozygous state by prenatal diagnosis.
Methods: GT was diagnosed in a 17 year old Omani female at the Sultan Qaboos University Hospital. The diagnosis of GT was based on clinical features, platelet aggregometry and biochemical studies. Platelet surface expression of GPIIb/IIIa was also studied by flowcytometry. Molecular studies performed at Medical Genetics Department, Tsukuba University, Japan, include DNA sequencing of all exons and exon-intron junctions of ITGA2B and ITGB3 of the two genes by the ABI 3100 Genetic Analyzer®. [Applied Biosystems, Foster City, CA, USA]. Genomic DNA was also analyzed by Illumina Human-1 Bead Chip Illumina® (Illumina Inc., San Diego, CA, USA) to exclude the whole region of the two genes that could produce an apparent homozygous state.
Results: We have identified a novel nonsense causative mutation (Q694X) by sequencing the ITGB3 gene. [Figure 1a & b]. In addition, sequencing ITGB3 gene also revealed 2 SNPs (rs 3809863; IVS14+9C/T, rs 3809865; 3383T/A). The Micro-Array assay using Illumina Human-1 Bead chip excluded the possibility of deletion of these genes in chromosome 17 in this patient.
Summary/Conclusion: A stop codon was found in exon 13 of ITGB3 gene causing the translated protein to be abnormally shortened. It is hypothesized that the altered form of ITGB3 gene is both extremely unstable and rapidly degraded after its biosynthesis, leading to a loss of function of the protein. Further RNA expression studies, transfection tests and cDNA sequencing are ongoing to elucidate the molecular mechanisms responsible for GT.
معرّف المصادر الموحد
http://www.bloodjournal.org/content/112/11/4540DOI/handle
http://hdl.handle.net/10576/5504المجموعات
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