title: Genetic variants in the noncoding region of RPS19 gene in Diamond-Blackfan anemia: potential implications for phenotypic heterogeneity.
abstract: Mutations in the RPS19 gene have been identified in 25% of individuals affected by Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia characterized by an aregenerative anemia and a variety of malformations. More than 60 mutations in the five coding exons of RPS19 have been described to date. We previously reported a mutation (c.-1 + 26G>T) and an insertion at -631 upstream of ATG (c.-147_-146insGCCA) in the noncoding region. Because DBA phenotype is extremely heterogeneous from silent to severe and because haploinsufficiency seems to play a role in this process, it is likely that genetic variations in the noncoding regions affecting translation of RPS19 can modulate the phenotypic expression of DBA. However, to date, very few studies have addressed this question comprehensively. In this study, we performed detailed sequence analysis of the RPS19 gene in 239 patients with DBA and 110 of their relatives. We found that 6.2% of the patients with DBA carried allelic variations upstream of ATG: 3.3% with c.-1 + 26G>T; 2.5% with c.-147_-146insGCCA; and 0.4% with c.-174G>A. Interestingly, the c.-147_-146insGCCA, which has been found in a black American and French Caribbean control population, was not found in 500 Caucasian control chromosomes we studied. However, it was found in association with the same haplotype distribution of four intronic polymorphisms in our patients with DBA. Although a polymorphism, the frequency of this variant in the patients with DBA and its association with the same haplotype raises the possibility that this polymorphism and the other genetic variations in the noncoding region could play a role in DBA pathogenesis.
authors.affiliation: INSERM U790, Villejuif, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Crétien
authors.forename: Alexis
authors.initials: A
authors.lastname: Proust
authors.forename: Jean
authors.initials: J
authors.lastname: Delaunay
authors.forename: Patricia
authors.initials: P
authors.lastname: Rincé
authors.forename: Thierry
authors.initials: T
authors.lastname: Leblanc
authors.forename: Rolande
authors.initials: R
authors.lastname: Ducrocq
authors.forename: Maud
authors.initials: M
authors.lastname: Simansour
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marie
authors.forename: Hannah
authors.initials: H
authors.lastname: Tamary
authors.forename: Jörg
authors.initials: J
authors.lastname: Meerpohl
authors.forename: Charlotte
authors.initials: C
authors.lastname: Niemeyer
authors.forename: Hanna
authors.initials: H
authors.lastname: Gazda
authors.forename: Colin
authors.initials: C
authors.lastname: Sieff
authors.forename: Sarah
authors.initials: S
authors.lastname: Ball
authors.forename: Gil
authors.initials: G
authors.lastname: Tchernia
authors.forename: Narla
authors.initials: N
authors.lastname: Mohandas
authors.forename: Lydie
authors.initials: L
authors.lastname: Da Costa
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D012269:Ribosomal Proteins / Q000235:genetics*
chemical_list: D012269:Ribosomal Proteins; C040343:ribosomal protein S19