Mutations in the RNA Component of RNase MRP Cause a Pleiotropic Human Disease, Cartilage-Hair Hypoplasia

Ridanpää, Maaret; Eenennaam, Hans van; Pelin, Katarina; Chadwick, Robert B.; Johnson, Cheryl K.; Yuan, Bo; vanVenrooij, Walther; Pruijn, Ger J. M.; Salmela, Riika; Rockas, Susanna; Mäkitie, Outi; Kaitila, Ilkka; Chapelle, Albert de la

doi:10.1016/s0092-8674(01)00205-7

Cited by 451 publications

(347 citation statements)

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“…They speculated that deregulation of these genes and the pathway that they were part of, could be the causative abnormality in 5q-syndrome patients. This idea was supported by previous findings that genetic defects of ribosomal genes were implicated in congenital anemias including dyskeratosis congenita, 12 cartilage-hair hypoplasia, 13 DiamondBlackfan anemia 14 and Shwachman-Diamond syndrome. 15,16 The importance of RPS14 haplo-insufficency as a causative event in 5q-syndrome was then shown by Ebert et al using RNAi to selectively inhibit each of the 40 genes within the deleted region.…”

supporting

confidence: 61%

Defective ribosome biogenesis in myelodysplastic syndromes

Galili¹,

Qasim²,

Raza³

2009

Haematologica

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M alignant disorders are poorly understood at the biological level in general, and myelodysplastic syndromes (MDS), a heterogeneous clonal stem cell disorder, in particular, are further confounded by representing a group of diseases rather than a single entity with clinical and biological heterogeneity within each subtype. The basis for grouping these assorted diseases under one MDS umbrella is the clinical presentation of variable cytopenias despite a generally cellular and dysplastic marrow. Diagnosis is based on bone marrow morphology, percentage of blasts, unexplained cytopenias and cytogenetics. These components have been used to classify the disease (French-American British 1 or FAB and World Health Organization 2 or WHO classifications) and to predict prognosis (International Prognostic Scoring System 3 or IPSS). The typical patient is elderly; thus with the increase in our aging population, the incidence of MDS has now surpassed that of acute myeloid leukemia (AML). Approximately 30% of MDS patients will progress to AML, but the majority die from infection or bleeding due to an increasing profundity of the cytopenias. The paradox of MDS is that despite peripheral cytopenia, the marrow is most often hypercellular. The initial breakthrough in understanding the biological basis of this paradox came with the demonstration that, in MDS, bone marrow cells were not only rapidly proliferating, but also undergoing excessive apoptosis. [4][5][6][7] As a result, the maturing hematopoietic cells are eliminated in the marrow and do not reach the peripheral blood, accounting for the cytopenias in the presence of a cellular marrow composed of mostly apoptotic cells. Furthermore, it was demonstrated that multiple cytokines involved in mediating apoptosis and proliferation are deregulated in MDS marrows. [7][8][9] While the MDS cell itself probably contributes, recent insights suggest that it is the bone marrow microenvironment that is also responsible for potentiating disease pathology and progression through cytokine imbalance. In summary then, MDS appears to be a disease of both the seed and the soil (the cell and its microenvironment) where peripheral cytopenias appear to be the result of an increased proliferation-increased apoptosis in the clonal cells and deregulated proapoptotic and trophic cytokines in the marrow.Approximately half the patients with MDS present with recurring cytogenetic abnormalities most commonly affecting chromosomes 5, 7, 8, and 20. These have been shown to greatly affect prognosis and survival. 3 Despite the presence of these well recognized karyotypic aberrations, genetic mutations that accompany them have not been well understood and, in fact, mutation in a specific biological pathway that is common to multiple MDS subtypes has not been identified. In short, apoptosis has remained the sole unifying biological characteristic of the disease.Recently, however, a possible cohesive genetic explanation for this increased apoptosis has been taking shape. Initial hints began with the study of pat...

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supporting

confidence: 61%

Defective ribosome biogenesis in myelodysplastic syndromes

Galili¹,

Qasim²,

Raza³

2009

Haematologica

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“…60 In 2001, Ridanpää et al identified mutations in the untranslated RMRP gene as causative for this pleiotropic disease, with an ancient founder mutation in Finland. 61 RMRP encodes the RNA component of the mitochondrial RNA processing complex (RNase MRP), which is primarily located in the nucleolus and is classified as a snoRNA. snoRNAs form small nucleolar ribonucleoprotein complexes (snoRNPs) within the nucleolus and are involved in various steps in the synthesis of ribosomal RNA.…”

Section: Cartilage Hair Hypoplasiamentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

683

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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“…By inference, it is assumed that the RNA subunit of MRP is also responsible for catalysis (13). MRP is also an essential endonuclease (52,53) that processes mostly rRNA, but also some mRNAs and other substrates (Table 2).…”

Section: Function and Substratesmentioning

confidence: 99%

Ribonucleases P/MRP and the Expanding Ribonucleoprotein World

et al. 2012

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SummaryOne of the hallmarks of life is the widespread use of certain essential ribozymes. The ubiquitous ribonuclease P (RNase P) and eukaryotic RNase MRP are essential complexes where a structured, noncoding RNA acts in catalysis. Recent discoveries have elucidated the three-dimensional structure of the ancestral ribonucleoprotein complex, suggested the possibility of a proteinonly composition in organelles, and even noted the absence of RNase P in a non-free-living organism. With respect to these last two findings, import mechanisms for RNases P/MRP into mitochondria have been demonstrated, and RNase P is present in organisms with some of the smallest known genomes. Together, these results have led to an ongoing debate regarding the precise definition of how ''essential'' these ribozymes truly are. IUBMBIUBMB Life, 64(6): [521][522][523][524][525][526][527][528] 2012

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Mutations in the RNA Component of RNase MRP Cause a Pleiotropic Human Disease, Cartilage-Hair Hypoplasia

Cited by 451 publications

References 40 publications

Defective ribosome biogenesis in myelodysplastic syndromes

Defective ribosome biogenesis in myelodysplastic syndromes

Ribosomopathies: human disorders of ribosome dysfunction

Ribonucleases P/MRP and the Expanding Ribonucleoprotein World

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