title: Diversity of Glanzmann thrombasthenia in southern India: 10 novel mutations identified among 15 unrelated patients.
abstract: BACKGROUND
  Glanzmann thrombasthenia (GT) is a congenital bleeding disorder caused by either a lack or dysfunction of the platelet integrin alphaIIbbeta3.
  
  
  OBJECTIVE
  To determine the molecular basis of GT in patients from southern India.
  
  
  METHODS
  Fifteen unrelated patients whose diagnosis was consistent with GT were evaluated.
  
  
  RESULTS
  Platelet surface expression of alphaIIbbeta3 was < 10%, 10%-50%, and > 50% of controls in five, nine, and one patient(s), respectively. Immunoblotting of the platelet lysates showed no alphaIIb in 14 patients, and no beta3 in 10 patients, although severely reduced in four patients. Platelet fibrinogen was undetectable in 13 patients, and severely reduced in one patient. One patient showed normal surface alphaIIbbeta3 expression, and normal alphaIIb, beta3 and fibrinogen levels in the lysate. Ten novel candidate disease-causing mutations were identified in 11 patients. The missense mutations included Gly128Ser, Ser287Leu, Gly357Ser, Arg520Trp, Leu799Arg in alphaIIb, and Cys575Gly in beta3. We have already shown that Gly128Ser, Ser287Leu, and Gly357Ser mutations variably affect alphaIIbbeta3 surface expression. The Cys575Gly mutation may disrupt the disulphide link with Cys586 to cause the GT phenotype. The molecular pathology of the other missense mutations is not clear. Two nonsense mutations, Trp-16Stop and Glu715Stop in alphaIIb, and a 7-bp deletion (330-336TCCCCAG) in beta3 are predicted to result in truncated proteins. An IVS15(-1)G --> A mutation in alphaIIb induced a cryptic splice site as confirmed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Thirteen polymorphisms were also identified (five in alphaIIb and eight in beta3), among which five were novel.
  
  
  CONCLUSIONS
  While identifying a significant number of novel mutations causing GT, this study confirms the genetic heterogeneity of the disorder in southern India.
authors.affiliation: Department of Hematology, Christtian Medical College, Vellore, India.
authors.forename: E J R
authors.initials: EJ
authors.lastname: Nelson
authors.forename: S C
authors.initials: SC
authors.lastname: Nair
authors.forename: H
authors.initials: H
authors.lastname: Peretz
authors.forename: B S
authors.initials: BS
authors.lastname: Coller
authors.forename: U
authors.initials: U
authors.lastname: Seligsohn
authors.forename: M
authors.initials: M
authors.lastname: Chandy
authors.forename: A
authors.initials: A
authors.lastname: Srivastava
mesh_terms: D000293:Adolescent; D000328:Adult; D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005340:Fibrinogen / Q000096:biosynthesis; D006801:Humans; D008297:Male; D009154:Mutation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics*; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D013915:Thrombasthenia / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen