title: Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia.
abstract: Diamond-Blackfan anemia (DBA) is an inherited form of pure red cell aplasia that usually presents in infancy or early childhood and is associated with congenital malformations in ∼30-50% of patients. DBA has been associated with mutations in nine ribosomal protein (RP) genes in about 53% of patients. We completed a large-scale screen of 79 RP genes by sequencing 16 RP genes (RPL3, RPL7, RPL8, RPL10, RPL14, RPL17, RPL19, RPL23A, RPL26, RPL27, RPL35, RPL36A, RPL39, RPS4X, RPS4Y1, and RPS21) in 96 DBA probands. We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities. This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits. We also found a deletion in RPL19 and missense mutations in RPL3 and RPL23A, which may be variants of unknown significance. Together with RPL5, RPL11, and RPS7, RPL26 is the fourth RP regulating p53 activity that is linked to DBA.
authors.affiliation: Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, 3 BlackfanCircle, Boston, MA 02115, USA. hanna.gazda@childrens.harvard.edu
authors.forename: Hanna T
authors.initials: HT
authors.lastname: Gazda
authors.forename: Milena
authors.initials: M
authors.lastname: Preti
authors.forename: Mee Rie
authors.initials: MR
authors.lastname: Sheen
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: O'Donohue
authors.forename: Adrianna
authors.initials: A
authors.lastname: Vlachos
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
authors.forename: Antonis
authors.initials: A
authors.lastname: Kattamis
authors.forename: Leana
authors.initials: L
authors.lastname: Doherty
authors.forename: Michael
authors.initials: M
authors.lastname: Landowski
authors.forename: Christopher
authors.initials: C
authors.lastname: Buros
authors.forename: Roxanne
authors.initials: R
authors.lastname: Ghazvinian
authors.forename: Colin A
authors.initials: CA
authors.lastname: Sieff
authors.forename: Peter E
authors.initials: PE
authors.lastname: Newburger
authors.forename: Edyta
authors.initials: E
authors.lastname: Niewiadomska
authors.forename: Michal
authors.initials: M
authors.lastname: Matysiak
authors.forename: Bertil
authors.initials: B
authors.lastname: Glader
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: D000015:Abnormalities, Multiple / Q000235:genetics*; D029503:Anemia, Diamond-Blackfan / Q000235:genetics* / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D016368:Frameshift Mutation / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D012335:RNA, Ribosomal / Q000235:genetics*; D034741:RNA, Small Interfering; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D012335:RNA, Ribosomal; D034741:RNA, Small Interfering; C489216:RPL26 protein, human; C000716547:RPL3 protein, human; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; C549166:ribosomal protein L5, human