Marrow failure: a window into ribosome biology

Abstract

Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita are inherited syndromes characterized by marrow failure, congenital anomalies, and cancer predisposition. Genetic and molecular studies have uncovered distinct abnormalities in ribosome biogenesis underlying each of these 3 disorders. How defects in ribosomes, the essential organelles required for protein biosynthesis in all cells, cause tissue-specific abnormalities in human disease remains a question of fundamental scientific and medical importance. Here we review the overlapping and distinct clinical features of these 3 syndromes and discuss current knowledge regarding the ribosomal pathways disrupted in each of these disorders. We also explore the increasing complexity of ribosome biology and how this informs our understanding of developmental biology and human disease.

Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes

“…14,15 Identification of the cell types specifically affected by dysfunction of ribosomal genes will thus be critical in deciphering the underlying molecular mechanisms driving disease pathology, ultimately enabling targeted therapies. However, progress in understanding the pathophysiology of SDS is limited by the lack of a robust mammalian model faithfully recapitulating neutropenia.…”

Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features

“…Several other IBMFSs are also caused by an abnormal translational machinery. These include Diamond-Blackfan anemia and the canonical SDS (29). While all these disorders (and others) are associated with mutations that affect 40S or 60S ribosomal subunits and/or their assembly (with the exception of 2 sporadic cases of aplastic anemia that were mutated in another SRP subunit [SRP72] [ref.…”

Kri1l: a novel gene that links defective ribosome biogenesis to impaired hematopoiesis through excessive autophagy

“…For example, the developmental defects caused by RPS14 haploinsufficiency in 5q-syndrome and the loss of Rps19/Rpl11 in DiamondBlackfan anemia have been shown to depend on the activation of p53 [2]. Rpl22 and its paralog Rpl22l1 regulate the generation of hematopoietic stem cells (HSC) by antagonistically regulating the translation of Smad1, which is critical for induction of the transcription factor Runx1 that drives HSC emergence [3].…”