Molecular diversity of Glanzmann thrombasthenia in Southern India: New insights into mRNA splicing and structure-function correlations of αIIbβ3 integrin (ITGA2B, ITGB3)

Hava Peretz, Nurit Rosenberg, Meytal Landau, Saly Usher, Everette J.R. Nelson, Ronit Mor-Cohen, Deborah L. French, Beau W. Mitchell, Sukesh C. Nair, Mammen Chandy, Barry S. Coller, Alok Srivastava, Uri Seligsohn

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

The molecular basis of Glanzmann thrombasthenia (GT) was studied in 40 families from southern India. Of 23 identified mutations (13 in the αIIb (ITGA2B) gene and 10 in the β3 (ITGB3) gene), 20 were novel and three were described previously. Three mutations in the β3 gene-p.Leu143Trp (Leu117Trp), p.Tyr307Stop (Tyr281Stop), and p.Arg119Gln (Arg93Gln)-were detected in 12, three, and two families, respectively, with definite founder effects observed for the first two mutations. Alternative splicing was predicted in silico for the normal variant and a missense variant of the β3 gene, and for 10/11 frameshift or nonsense mutations in αIIb or β3. The prediction was confirmed experimentally for a c.2898_2902dupCCCCT mutation in exon 28 of the αIIb gene that induced exon skipping. Seven out of nine missense mutations substituted highly conserved amino acids buried in the proteins' cores, predicting structural abnormalities. Among these, a β3 substitution, p.Cys39Gly (Cys13Gly) was found to cause intracellular degradation of the β3 subunit, in contrast to previous findings that mutations at Cys435, the partner of Cys13 in a disulfide bond, cause constitutive activation of αIIbβ3. The two patients with a β3 Arg93Gln mutation had normal clot retraction, consistent with a recent finding that this substitution is associated with normal surface expression of αIIbβ3. In conclusion, this study demonstrates that a variety of mutations account for GT in southern Indian patients, provides new insights into mRNA splicing, and highlights the role of specific amino acids in structure-function correlations of αIIbβ3.

Original languageEnglish (US)
Pages (from-to)359-369
Number of pages11
JournalHuman Mutation
Volume27
Issue number4
DOIs
StatePublished - Apr 2006
Externally publishedYes

Keywords

  • Founder effects
  • Glanzmann thrombasthenia
  • Integrin
  • Phylogenetic tree
  • Southern India
  • Splicing
  • Structure-function correlation
  • αIIbβ3 (ITGA2B, ITGB3)

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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