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Molecular diversity of Glanzmann thrombasthenia in southern India: new insights into mRNA splicing and structure–function correlations of α IIb β 3 integrin ( ITGA2B, ITGB3 )
Author(s) -
Peretz Hava,
Rosenberg Nurit,
Landau Meytal,
Usher Saly,
Nelson Everette J.R.,
MorCohen Ronit,
French Deborah L.,
Mitchell Beau W.,
Nair Sukesh C.,
Chandy Mammen,
Coller Barry S.,
Srivastava Alok,
Seligsohn Uri
Publication year - 2006
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20304
Subject(s) - exon , biology , missense mutation , genetics , frameshift mutation , rna splicing , gene , mutation , platelet glycoprotein gpiib iiia complex , thrombasthenia , microbiology and biotechnology , coding region , alternative splicing , silent mutation , nonsense mutation , integrin , platelet , receptor , rna , platelet aggregation , immunology
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. Hum Mutat 27(4), 359–369, 2006. © 2006 Wiley‐Liss, Inc.