Bone marrow cells from patients with Shwachman‐Diamond syndrome abnormally express genes involved in ribosome biogenesis and RNA processing

Rujkijyanont, Piya; Adams, Sally-Lin; Beyene, Joseph; Dror, Yigal

doi:10.1111/j.1365-2141.2009.07692.x

Cited by 37 publications

(42 citation statements)

References 66 publications

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“…44 In patient bone marrow samples, translationrelated gene expression is the most prominently regulated gene cluster compared with a number of other pathways known to be defective in various marrow failure conditions, including hematopoietic transcription factors and telomere maintenance. 45 SDS cells have also been noted to have abnormal expression of multiple genes involved in ribosome biogenesis and rRNA and mRNA processing and to have decreased expression of several ribosomal protein genes involved in cell growth and survival, including RPS9, RPS20, RPL6, RPL15, RPL22, RPL23, and RPL29. 45 Furthermore, SBDS has been shown to cosediment with the 60S ribosomal precursor subunit in sucrose gradients and to associate with the 28S rRNA, which is a component of the 60S subunit.…”

Section: Q؊ Syndromementioning

confidence: 99%

“…45 SDS cells have also been noted to have abnormal expression of multiple genes involved in ribosome biogenesis and rRNA and mRNA processing and to have decreased expression of several ribosomal protein genes involved in cell growth and survival, including RPS9, RPS20, RPL6, RPL15, RPL22, RPL23, and RPL29. 45 Furthermore, SBDS has been shown to cosediment with the 60S ribosomal precursor subunit in sucrose gradients and to associate with the 28S rRNA, which is a component of the 60S subunit. 44 Although these findings provide evidence for a role of SBDS in ribosome biogenesis, SBDS is a multifunctional protein, and nonribosomal activities may play a dominant role in the clinical phenotype.…”

Section: Q؊ Syndromementioning

confidence: 99%

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Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

698

726

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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Section: Q؊ Syndromementioning

confidence: 99%

Section: Q؊ Syndromementioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

698

726

View full text Add to dashboard Cite

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“…Loss of rpl3 phenocopies the p53-independent sbds pancreatic phenotype Significant changes in the expression of ribosome-related genes were previously noted in the analysis of human SDS patient bone marrow samples (Rujkijyanont et al, 2009). Similar to that report, we identified ribosomal protein L3 (rpl3) as a gene downregulated in the absence of Sbds.…”

Section: Loss Of Sbds Is Associated With a Broad Change In Ribosome-rmentioning

confidence: 99%

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

et al. 2012

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SUMMARYMutations in the human Shwachman-Bodian-Diamond syndrome (SBDS) gene cause defective ribosome assembly and are associated with exocrine pancreatic insufficiency, chronic neutropenia and skeletal defects. However, the mechanism underlying these phenotypes remains unclear. Here we show that knockdown of the zebrafish sbds ortholog fully recapitulates the spectrum of developmental abnormalities observed in the human syndrome, and further implicate impaired proliferation of ptf1a-expressing pancreatic progenitor cells as the basis for the observed pancreatic phenotype. It is thought that diseases of ribosome assembly share a p53-dependent mechanism. However, loss of p53 did not rescue the developmental defects associated with loss of zebrafish sbds. To clarify the molecular mechanisms underlying the observed organogenesis defects, we performed transcriptional profiling to identify candidate downstream mediators of the sbds phenotype. Among transcripts displaying differential expression, functional group analysis revealed marked enrichment of genes related to ribosome biogenesis, rRNA processing and translational initiation. Among these, ribosomal protein L3 (rpl3) and pescadillo (pes) were selected for additional analysis. Similar to knockdown of sbds, knockdown or mutation of either rpl3 or pes resulted in impaired expansion of pancreatic progenitor cells. The pancreatic phenotypes observed in rpl3-and pes-deficient embryos were also independent of p53. Together, these data suggest novel p53-independent roles for ribosomal biogenesis genes in zebrafish pancreas development.

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“…10 SDS results from mutations in the ubiquitously expressed, conserved Shwachman-Bedian-Diamond syndrome gene (SBDS). 11 The exact function of the SBDS protein remains unclear; however, in recent years, through studies of orthologs in yeast and Archaea 12,13 and patient bone marrow cells, [14][15][16] it has been postulated to function in RNA metabolism and ribosome biogenesis. SBDS is an essential gene in embryogenesis, 17 and SBDS has also been implicated in cell division 18,19 and cellular stress responses.…”

Section: Introductionmentioning

confidence: 99%

Sbds is required for Rac2-mediated monocyte migration and signaling downstream of RANK during osteoclastogenesis

Leung

Cuddy

Wang

et al. 2011

Blood

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Shwachman-Diamond syndrome (SDS) results from mutations in the SBDS gene, characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities. Neutropenia and neutrophil dysfunction are hallmark features of SDS; however, causes for the bone defects are unknown. Dysfunction of boneresorbing osteoclasts, formed by the fusion of monocytic progenitors derived from the same granulocytic precursors as neutrophils, could be responsible. We report that Sbds is required for in vitro and in vivo osteoclastogenesis (OCG).Sbds-null murine monocytes formed osteoclasts of reduced number and size because of impaired migration and fusion required for OCG. Phenotypically, Sbdsnull mice exhibited low-turnover osteoporosis consistent with findings in SDS patients. Western blotting of Rho GTPases that control actin dynamics and migration showed a 5-fold decrease in Rac2, whereas Rac1, Cdc42, and RhoA were unchanged or only mildly reduced. Although migration was rescued on Rac2 supplementation, OCG was not. This was attributed to impaired signaling downstream of receptor activator of nuclear factor-B (RANK) and reduced expression of the RANK-ligand-dependent fusion receptor DC-STAMP. We conclude that Sbds is required for OCG by regulating monocyte migration via Rac2 and osteoclast differentiation signaling downstream of RANK. Impaired osteoclast formation could disrupt bone homeostasis, resulting in skeletal abnormalities seen in SDS patients. (Blood. 2011;117(6): 2044-2053) IntroductionShwachman-Diamond syndrome (SDS) is an autosomal recessive disorder with hallmark features of bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities. [1][2][3] Neutropenia is the most common clinical manifestation of bone marrow failure, but patients may also experience pancytopenia, anemia, and thrombocytopenia, and be at increased risk of developing aplastic anemia and acute myeloid leukemia. 4 In early crosssectional studies, metaphyseal dysostosis was observed in 40% to 80% of SDS patients, and rib and/or thoracic cage abnormalities in 30% to 50% of SDS patients. [5][6][7] More recently, in a longitudinal study, all of the SDS patients studied displayed various skeletal abnormalities, including delayed appearance of secondary ossification centers, variable widening, and irregularity of the metaphyses in early childhood followed by progressive thickening and irregularity of the growth plates, and generalized osteopenia. 8 In addition, a subset of patients showed early signs of osteoporotic vertebral deformities and disturbances in bone homeostasis manifesting in low-turnover osteoporosis. 8,9 Oral and dental diseases and conditions, including periodontitis, delayed eruption of the permanent dentition, increased caries risk in primary and permanent dentitions, and increased soft tissue pathoses, have also been reported. 10 SDS results from mutations in the ubiquitously expressed, conserved Shwachman-Bedian-Diamond syndrome gene (SBDS). 11 The exact function of the SBDS protein remains unclear; h...

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Bone marrow cells from patients with Shwachman‐Diamond syndrome abnormally express genes involved in ribosome biogenesis and RNA processing

Cited by 37 publications

References 66 publications

Ribosomopathies: human disorders of ribosome dysfunction

Ribosomopathies: human disorders of ribosome dysfunction

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

Sbds is required for Rac2-mediated monocyte migration and signaling downstream of RANK during osteoclastogenesis

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