A unique combination of inhibitory and partially activating mutations in β3 of a patient with variant-type Glanzmann thrombasthenia

Nurden, Alan T.; Fernandes, Helder; Fiore, Mathieu; Vinciguerra, Christine; Martins, Nathalie; Sirvain-Trukniewicz, Peggy; Couloux, Arnaud; Heilig, Roland; Pillois, Xavier

doi:10.3109/09537101003771528

Cited by 2 publications

(2 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it is interesting to note that C575‐C584 and C614‐C624 disulfide bonds occupy the same 5‐6 (or 7‐8 in the alternative model) positions in ITGB3 IEGF‐3 and IEGF‐4 domains, respectively 28 . GT mutations disrupting these conserved disulfide bonds caused markedly reduced production of constitutively active αIIbβ3 with defective αIIbβ3 maturation 29‐31 …”

Section: Discussionmentioning

confidence: 99%

“…28 GT mutations disrupting these conserved disulfide bonds caused markedly reduced production of constitutively active αIIbβ3 with defective αIIbβ3 maturation. [29][30][31] Of note, Y141C and C547W mutations have been detected exclusively in GT families from Pakistan and India, part of the same Indo-Pak subcontinent. Particularly, the three different Pakistani GT families harboring the same C547W mutation co-localize geographically in the same region (Punjab province of Pakistan) and share the same parent ethnic group (Rajput caste) suggesting the possibility of a founder effect.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Two homozygous missense mutations in ITGB3 gene as a cause of Glanzmann Thrombasthenia in four consanguineous Pakistani pedigrees

Ali

Gul

Amar

et al. 2020

Int J Lab Hematology

View full text Add to dashboard Cite

Introduction Glanzmann thrombasthenia (GT) is most common of inherited platelet disorders, resulting from quantitative/qualitative defects in platelet surface integrin αIIbβ3, encoded by ITGA2B and ITGB3 genes. Little is known about clinical and molecular characteristics of GT patients from highly consanguineous Pakistani population. Methods This study analyzed the clinical and molecular spectrum of six GT patients from four unrelated but consanguineous families. Platelet surface expression of αIIbβ3 integrin was determined using flow cytometry analysis. ITGA2B and ITGB3 genes were screened for causative mutations by DNA sequencing. Detected mutations were characterized for their pathogenicity using a variety of in silico tools. Results Glanzmann thrombasthenia patients in this study generally presented early in life, had a severe course of clinical disease with transfusion dependency for management of bleeding episodes. Molecular analysis revealed 2 homozygous missense mutations in ITGB3 gene, c.422 A˃G (p.Y141C) in three GT patients from a single pedigree with familial segregation and c.1641 C>G (p.C547W) in three unrelated GT patients from three families manifesting type I GT with severe reduction in platelet αIIbβ3 levels. In silico pathogenicity predictions, multiple sequence alignment and 3D protein modeling unanimously suggested deleterious nature of the detected mutations, possibly due to aberrant disulfide bonding. Of note, clinical diversity was observed even among GT patients with same mutation in GT1 family. Conclusion This study provides an initial yet important account of clinical and genetic characterization of GT in local patients which may spark further studies to help molecular diagnosis, optimal disease management, and genetic counseling based prevention efforts.

show abstract

Section: Discussionmentioning

confidence: 99%