title: Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide variations in phenotypic expression.
abstract: Mutations of the ribosomal protein S19 (RPS19) gene were recently identified in 10 patients with Diamond Blackfan anemia (DBA). To determine the prevalence of mutations in this gene in DBA and to begin to define the molecular basis for the observed variable clinical phenotype of this disorder, the genomic sequence of the 6 exons and the 5' untranslated region of the RPS19 gene was directly assessed in DBA index cases from 172 new families. Mutations affecting the coding sequence of RPS19 or splice sites were found in 34 cases (19.7%), whereas mutations in noncoding regions were found in 8 patients (4.6%). Mutations included nonsense, missense, splice sites, and frameshift mutations. A hot spot for missense mutations was identified between codons 52 and 62 of the RPS19 gene in a new sequence consensus motif W-[YFW]-[YF]-x-R-[AT]-A-[SA]-x-[AL]-R-[HRK]-[ILV]-Y. No correlation between the nature of mutations and the different patterns of clinical expression, including age at presentation, presence of malformations, and therapeutic outcome, could be documented. Moreover, RPS19 mutations were also found in some first-degree relatives presenting only with isolated high erythrocyte adenosine deaminase activity and/or macrocytosis. The lack of a consistent relationship between the nature of the mutations and the clinical phenotype implies that yet unidentified factors modulate the phenotypic expression of the primary genetic defect in families with RPS19 mutations.
authors.affiliation: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. tnwillig@lbl.gov
authors.forename: T N
authors.initials: TN
authors.lastname: Willig
authors.forename: N
authors.initials: N
authors.lastname: Draptchinskaia
authors.forename: I
authors.initials: I
authors.lastname: Dianzani
authors.forename: S
authors.initials: S
authors.lastname: Ball
authors.forename: C
authors.initials: C
authors.lastname: Niemeyer
authors.forename: U
authors.initials: U
authors.lastname: Ramenghi
authors.forename: K
authors.initials: K
authors.lastname: Orfali
authors.forename: P
authors.initials: P
authors.lastname: Gustavsson
authors.forename: E
authors.initials: E
authors.lastname: Garelli
authors.forename: A
authors.initials: A
authors.lastname: Brusco
authors.forename: C
authors.initials: C
authors.lastname: Tiemann
authors.forename: J L
authors.initials: JL
authors.lastname: Pérignon
authors.forename: C
authors.initials: C
authors.lastname: Bouchier
authors.forename: L
authors.initials: L
authors.lastname: Cicchiello
authors.forename: N
authors.initials: N
authors.lastname: Dahl
authors.forename: N
authors.initials: N
authors.lastname: Mohandas
authors.forename: G
authors.initials: G
authors.lastname: Tchernia
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002675:Child, Preschool; D005199:Fanconi Anemia / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012269:Ribosomal Proteins / Q000235:genetics*
chemical_list: D012269:Ribosomal Proteins; C040343:ribosomal protein S19