Abnormalities of the large ribosomal subunit protein, rpl35a, in diamond-blaekfan anemia

Jason E. Farrar; Michelle Nater; Emi Caywood; Michael A. Mcdevitt; Jeanne Kowalski; Clifford M. Takemoto; C. Conover Talbot; Paul Meltzer; Diane Esposito; Alan H. Beggs; Hal E. Schneider; Agnieszka Grabowska; Sarah E. Ball; Edyta Niewiadomska; Colin A. Sieff; Adrianna Vlachos; Eva Atsidaftos; Steven R. Ellis; Jeffrey M. Lipton; Hanna T. Gazda; Robert J. Arceci

doi:10.1182/blood-2008-02-140012

Abnormalities of the large ribosomal subunit protein, rpl35a, in diamond-blaekfan anemia

Jason E. Farrar, Michelle Nater, Emi Caywood, Michael A. Mcdevitt, Jeanne Kowalski, Clifford M. Takemoto, C. Conover Talbot, Paul Meltzer, Diane Esposito, Alan H. Beggs, Hal E. Schneider, Agnieszka Grabowska, Sarah E. Ball, Edyta Niewiadomska, Colin A. Sieff, Adrianna Vlachos, Eva Atsidaftos, Steven R. Ellis, Jeffrey M. Lipton, Hanna T. GazdaRobert J. Arceci

Research output: Contribution to journal › Article › peer-review

174 Scopus citations

Abstract

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17are mutated in approximately one-third of patients. We used a candidate gene strategy combining highresolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition.

Original language	English (US)
Pages (from-to)	1582-1592
Number of pages	11
Journal	Blood
Volume	112
Issue number	5
DOIs	https://doi.org/10.1182/blood-2008-02-140012
State	Published - Sep 1 2008
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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Farrar, J. E., Nater, M., Caywood, E., Mcdevitt, M. A., Kowalski, J., Takemoto, C. M., Talbot, C. C., Meltzer, P., Esposito, D., Beggs, A. H., Schneider, H. E., Grabowska, A., Ball, S. E., Niewiadomska, E., Sieff, C. A., Vlachos, A., Atsidaftos, E., Ellis, S. R., Lipton, J. M., ... Arceci, R. J. (2008). Abnormalities of the large ribosomal subunit protein, rpl35a, in diamond-blaekfan anemia. Blood, 112(5), 1582-1592. https://doi.org/10.1182/blood-2008-02-140012

Farrar, JE, Nater, M, Caywood, E, Mcdevitt, MA, Kowalski, J, Takemoto, CM, Talbot, CC, Meltzer, P, Esposito, D, Beggs, AH, Schneider, HE, Grabowska, A, Ball, SE, Niewiadomska, E, Sieff, CA, Vlachos, A, Atsidaftos, E, Ellis, SR, Lipton, JM, Gazda, HT & Arceci, RJ 2008, 'Abnormalities of the large ribosomal subunit protein, rpl35a, in diamond-blaekfan anemia', Blood, vol. 112, no. 5, pp. 1582-1592. https://doi.org/10.1182/blood-2008-02-140012

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title = "Abnormalities of the large ribosomal subunit protein, rpl35a, in diamond-blaekfan anemia",

abstract = "Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17are mutated in approximately one-third of patients. We used a candidate gene strategy combining highresolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition.",

author = "Farrar, {Jason E.} and Michelle Nater and Emi Caywood and Mcdevitt, {Michael A.} and Jeanne Kowalski and Takemoto, {Clifford M.} and Talbot, {C. Conover} and Paul Meltzer and Diane Esposito and Beggs, {Alan H.} and Schneider, {Hal E.} and Agnieszka Grabowska and Ball, {Sarah E.} and Edyta Niewiadomska and Sieff, {Colin A.} and Adrianna Vlachos and Eva Atsidaftos and Ellis, {Steven R.} and Lipton, {Jeffrey M.} and Gazda, {Hanna T.} and Arceci, {Robert J.}",

year = "2008",

month = sep,

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doi = "10.1182/blood-2008-02-140012",

language = "English (US)",

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T1 - Abnormalities of the large ribosomal subunit protein, rpl35a, in diamond-blaekfan anemia

AU - Farrar, Jason E.

AU - Nater, Michelle

AU - Caywood, Emi

AU - Mcdevitt, Michael A.

AU - Kowalski, Jeanne

AU - Takemoto, Clifford M.

AU - Talbot, C. Conover

AU - Meltzer, Paul

AU - Esposito, Diane

AU - Beggs, Alan H.

AU - Schneider, Hal E.

AU - Grabowska, Agnieszka

AU - Ball, Sarah E.

AU - Niewiadomska, Edyta

AU - Sieff, Colin A.

AU - Vlachos, Adrianna

AU - Atsidaftos, Eva

AU - Ellis, Steven R.

AU - Lipton, Jeffrey M.

AU - Gazda, Hanna T.

AU - Arceci, Robert J.

PY - 2008/9/1

Y1 - 2008/9/1

N2 - Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17are mutated in approximately one-third of patients. We used a candidate gene strategy combining highresolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition.

AB - Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17are mutated in approximately one-third of patients. We used a candidate gene strategy combining highresolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition.

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JO - Blood

JF - Blood

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ER -

Abnormalities of the large ribosomal subunit protein, rpl35a, in diamond-blaekfan anemia

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