Document Type

Article

Publication Date

8-1-2024

Identifier

DOI: 10.1172/jci.insight.172475

Abstract

Diamond-Blackfan anemia syndrome (DBA) is a ribosomopathy associated with loss-of-function variants in more than 20 ribosomal protein (RP) genes. Here, we report the genetic, functional, and biochemical dissection of 2 multigenerational pedigrees with variants in RPL17, a large ribosomal subunit protein-encoding gene. Affected individuals had clinical features and erythroid proliferation defects consistent with DBA. Further, RPL17/uL22 depletion resulted in anemia and micrognathia in zebrafish larvae, and in vivo complementation studies indicated that RPL17 variants were pathogenic. Lymphoblastoid cell lines (LCLs) derived from patients displayed a ribosomal RNA maturation defect reflecting haploinsufficiency of RPL17. The proteins encoded by RPL17 variants were not incorporated into ribosomes, but 10%-20% of 60S ribosomal subunits contained a short form of 5.8S rRNA (5.8SC), a species that is marginal in normal cells. These atypical 60S subunits were actively engaged in translation. Ribosome profiling showed changes of the translational profile, but those are similar to LCLs bearing RPS19 variants. These results link an additional RP gene to DBA. They show that ribosomes can be modified substantially by RPL17 haploinsufficiency but support the paradigm that translation alterations in DBA are primarily related to insufficient ribosome production rather than to changes in ribosome structure or composition.

Journal Title

JCI Insight

Volume

9

Issue

17

MeSH Keywords

Anemia, Diamond-Blackfan; Ribosomal Proteins; Humans; Zebrafish; Animals; Male; Female; Pedigree; Haploinsufficiency

Keywords

Bone marrow; Genetics; Hematology; RNA processing; Translation

Comments

This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Publisher's Link: https://insight.jci.org/articles/view/172475

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