title: Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients.
abstract: Diamond-Blackfan anemia (DBA), a congenital bone-marrow-failure syndrome, is characterized by red blood cell aplasia, macrocytic anemia, clinical heterogeneity, and increased risk of malignancy. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital anomalies that are present in approximately 30%-50% of patients. The disease has been associated with mutations in four ribosomal protein (RP) genes, RPS19, RPS24, RPS17, and RPL35A, in about 30% of patients. However, the genetic basis of the remaining 70% of cases is still unknown. Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7. In addition, we identified rare variants of unknown significance in three other genes, RPL36, RPS15, and RPS27A. Remarkably, careful review of the clinical data showed that mutations in RPL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11. We also demonstrate that mutations of RPL5, RPL11, or RPS7 in DBA cells is associated with diverse defects in the maturation of ribosomal RNAs in the large or the small ribosomal subunit production pathway, expanding the repertoire of ribosomal RNA processing defects associated with DBA.
authors.affiliation: Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA 02115, USA. hanna.gazda@childrens.harvard.edu
authors.forename: Hanna T
authors.initials: HT
authors.lastname: Gazda
authors.forename: Mee Rie
authors.initials: MR
authors.lastname: Sheen
authors.forename: Adrianna
authors.initials: A
authors.lastname: Vlachos
authors.forename: Valerie
authors.initials: V
authors.lastname: Choesmel
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: O'Donohue
authors.forename: Hal
authors.initials: H
authors.lastname: Schneider
authors.forename: Natasha
authors.initials: N
authors.lastname: Darras
authors.forename: Catherine
authors.initials: C
authors.lastname: Hasman
authors.forename: Colin A
authors.initials: CA
authors.lastname: Sieff
authors.forename: Peter E
authors.initials: PE
authors.lastname: Newburger
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Ball
authors.forename: Edyta
authors.initials: E
authors.lastname: Niewiadomska
authors.forename: Michal
authors.initials: M
authors.lastname: Matysiak
authors.forename: Jan M
authors.initials: JM
authors.lastname: Zaucha
authors.forename: Bertil
authors.initials: B
authors.lastname: Glader
authors.forename: Charlotte
authors.initials: C
authors.lastname: Niemeyer
authors.forename: Joerg J
authors.initials: JJ
authors.lastname: Meerpohl
authors.forename: Eva
authors.initials: E
authors.lastname: Atsidaftos
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Lipton
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Gleizes
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D006801:Humans; D009154:Mutation; D012269:Ribosomal Proteins / Q000235:genetics*; D054658:Ribosome Subunits, Large / Q000235:genetics; D054679:Ribosome Subunits, Small / Q000235:genetics; D013933:Thumb / Q000002:abnormalities*
chemical_list: D012269:Ribosomal Proteins; C027624:ribosomal protein L11; C029742:ribosomal protein L5