TY - JOUR
T1 - Ribosomal Protein Genes RPS10 and RPS26 Are Commonly Mutated in Diamond-Blackfan Anemia
AU - Doherty, Leana
AU - Sheen, Mee Rie
AU - Vlachos, Adrianna
AU - Choesmel, Valerie
AU - O'Donohue, Marie Françoise
AU - Clinton, Catherine
AU - Schneider, Hal E.
AU - Sieff, Colin A.
AU - Newburger, Peter E.
AU - Ball, Sarah E.
AU - Niewiadomska, Edyta
AU - Matysiak, Michal
AU - Glader, Bertil
AU - Arceci, Robert J.
AU - Farrar, Jason E.
AU - Atsidaftos, Eva
AU - Lipton, Jeffrey M.
AU - Gleizes, Pierre Emmanuel
AU - Gazda, Hanna T.
N1 - Funding Information:
This work was supported by a generous gift from The Manton Foundation and a grant from the French National Research Agency (Agence Nationale de la Recherche, RIBODBA project), as well as grants from the Daniella Maria Arturi Foundation, the Diamond Blackfan Anemia Foundation, the Pediatric Cancer Foundation (J.M.L.), the National Institutes of Health (NIH) (R01 HL 079571) (J.M.L., A.V., E.A.), and the Feinstein Institute for Medical Research at the North Shore Long Island Jewish General Clinical Research Center (M01 RR018535) (J.M.L., A.V., E.A.). DNA sequencing was performed by the Children's Hospital Boston Program in Genomics and the Molecular Genetics Core Facility supported by the Developmental Disabilities Research Center (NIH P30 HD18655) and the Harvard Neuromuscular Disease Project (NIH P50 NS040828), by the Children's Hospital Boston SNP Genotyping Facilities, and by the Diamond Blackfan Anemia Gene Discovery and Resequencing Project (National Heart, Lung, and Blood Institute Resequencing & Genotyping Service) (R109 MOHLKE). We thank Alan Beggs for many helpful discussions, advice, and support; Marie Arturi for stimulating DBA research collaboration; and all of the physicians and DBA patients for participating in the study.
PY - 2010/2/12
Y1 - 2010/2/12
N2 - Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in ∼30%-50% of patients. DBA has been associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing.
AB - Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in ∼30%-50% of patients. DBA has been associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing.
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U2 - 10.1016/j.ajhg.2009.12.015
DO - 10.1016/j.ajhg.2009.12.015
M3 - Article
C2 - 20116044
AN - SCOPUS:76049086340
SN - 0002-9297
VL - 86
SP - 222
EP - 228
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -