Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia

Hum Mutat. 2012 Jul;33(7):1037-44. doi: 10.1002/humu.22081. Epub 2012 Apr 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Anemia, Diamond-Blackfan / genetics*
  • Anemia, Diamond-Blackfan / metabolism*
  • Blotting, Northern
  • Blotting, Western
  • Frameshift Mutation / genetics*
  • HeLa Cells
  • Humans
  • RNA, Ribosomal / genetics*
  • RNA, Small Interfering
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • RNA, Ribosomal
  • RNA, Small Interfering
  • RPL26 protein, human
  • Ribosomal Proteins
  • Tumor Suppressor Protein p53
  • ribosomal protein L11
  • ribosomal protein L5, human