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Ribosomopathies are diseases caused by abnormalities in the structure or function of ribosomal component proteins or rRNA genes, or other genes whose products are involved in ribosome biogenesis.[1][2][3]


Ribosomal rRNA subunits

Ribosomes are essential for protein synthesis in all living organisms. Prokaryotic and eukaryotic ribosomes both contain a scaffold of ribosomal RNA (rRNA) on which are arrayed an extensive variety of ribosomal proteins (RP).[4] Ribosomopathies can arise from abnormalities of either rRNA or the various RPs.

The nomenclature of rRNA subunits is derived from each component's Svedberg unit, which is an ultracentrifuge sedimentation coefficient, that is affected by mass and also shape. These S units of the rRNA subunits cannot simply be added because they represent measures of sedimentation rate rather than of mass. Eukaryotic ribosomes are somewhat larger and more complex than prokaryotic ribosomes. The overall 80S eukaryotic rRNA structure is composed of a large 60S subunit (LSU) and a small 40S subunit (SSU).[5]

In humans, a single transcription unit separated by 2 internally transcribed spacers encodes a precursor, 45S. The precursor 45S rDNA is organized into 5 clusters (each has 30-40 repeats) on chromosomes 13, 14, 15, 21, and 22. These are transcribed in the nucleolus by RNA polymerase I. 45S is processed in the nucleus via 32S rRNA to 28S[6] and 5.8S,[7] and via 30S to 18S,[8] as shown in the diagram. 18S is a component of the ribosomal 40S subunit. 28S, 5.8S and 5S,[9] which is transcribed independently, are components of 60S. The 5S DNA occurs in tandem arrays (~200-300 true 5S genes and many dispersed pseudogenes); the largest is on chromosome 1q41-42. 5S rRNA is transcribed by RNA polymerase III.[5] It is not fully clear why rRNA is processed in this way rather than being directly transcribed as mature rRNA, but the sequential steps may have a role in the proper folding of rRNA or in subsequent RP assembly.

The products of this processing within the cell nucleus are the four principal types of cytoplasmic rRNA: 28S, 5.8S, 18S, and 5S subunits.[10]:291 and (cite)(cite) (Mammalian cells also have 2 types of mitochondrial rRNA molecules, 12S and 16S.) In humans, as in most eukaryotes, the 18S rRNA is a component of 40S ribosomal subunit, and the 60S large subunit contains three rRNA species (the 5S, 5.8S and 28S in mammals, 25S in plants). 60S rRNA acts as a ribozyme, catalyzing peptide bond formation, while 40S monitors the complementarity between tRNA anticodon and mRNA.


Abnormal ribosome biogenesis is linked to several human genetic diseases.

Ribosomopathy has been linked to skeletal muscle atrophy,[11] and underpins most Diamond–Blackfan anemia (DBA),[2] the X-linked subtype of dyskeratosis congenita (DKCX),[12][13] Treacher Collins syndrome (TCS),[2][14] Shwachman–Diamond syndrome (SDS)[15] and 5q- myelodysplastic syndrome.(5q- MDS),(cite)(cite) North American Indian childhood cirrhosis (NAIC),[16] isolated congenital asplenia (ICAS),[16][17][18][19] and Bowen–Conradi syndrome (BWCNS), CHARGE syndrome[20][21][22][23] and ANE syndrome (ANES).[24]

The associated chromosome, OMIM genotype, phenotype, and possible disruption points are shown:

name chromosome genotype[25] phenotype protein disruption(cite)(cite)
DBA1[25] 19q13.2 603474 105650 RPS19 30S to 18S[10]:291(cite)
DBA2 8p23-p22 unknown 606129
DBA3 10q22-q23 602412 610629 RPS24[26] 30S to 18S[10]:291(cite)
DBA4 15q 180472 612527 RPS17[27] 30S to 18S[10]:291
DBA5 3q29-qter 180468 612528 RPL35A[28] 32S to 5.8S/28S[10]:291(cite)
DBA6 1p22.1 603634 612561 RPL5[29] 32S to 5.8S/28S[10]:291
DBA7 1p36.1-p35 604175 612562 RPL11[29] 32S to 5.8S/28S[10]:291
DBA8 2p25 603658 612563 RPS7[29] 30S to 18S[10]:291
DBA9 6p 603632 613308 RPS10[25] 30S to 18S[30]
DBA10 12q 603701 613309 RPS26 30S to 18S[31]
DBA11 17p13 603704 614900 RPS26 30S to 18S[31]
DBA12 3p24 604174 615550 RPL15 45S to 32S[32]
DBA13 14q 603633 615909 RPS29
DKCX Xq28 300126 305000 dyskerin associated with both H/ACA small nucleolar RNA (snoRNA) and with the RNA component of TERC[33]
5q- 5q33.1 130620 153550 RPS14 30S to 18S[10]:291
SDS 7q11.21 607444 260400 SBDS 60S to 80S[10]:291
CHH 9p13.3 157660 250250 RMRP mitochondrial RNA processing
NAIC 16q22.1 607456 604901 cirhin partial loss of interaction between cirhin and NOL11[34]
ICAS 3p22.1 150370 271400 RPSA
BWCNS 12p13.31 611531 211180 EMG1 18S to 40S
CHARGE 8q12.1-q12.2; also 7q21.11 608892 214800 CHD7; also SEMA3E
ACES xxx xxx RBM28

Several ribosomopathies share features such as inherited bone marrow failure, which is characterized a reduced number of blood cells and by a predisposition to cancer.[5] Other features can include skeletal abnormalities and growth retardation.[16] However, clinically these diseases are distinct, and do not show a consistent set of features.[16]

Diamond–Blackfan anemia[edit]

With the exception of rare GATA1 genotypes,(cite) Diamond–Blackfan anemia (DBA) arises from a variety of mutations that cause ribosomopathies.[35]

Dyskeratosis congenita[edit]

The X-linked subtype of dyskeratosis congenita (DKCX)

Shwachman–Diamond syndrome[edit]

Shwachman–Diamond syndrome (SDS) is caused by bi-allelic mutations in the SBDS protein that affects its ability to couple GTP hydrolysis by the GTPase EFL1 to the release of eIF6 from the 60S subunit.[36] Clinically, SDS affects multiple systems, causing bony abnormalities, and pancreatic and neurocognitive dysfunction.[37] SBDS associates with the 60S subunit in human cells and has a role in subunit joining and translational activation in yeast models.

5q- myelodysplastic syndrome[edit]

5q- myelodysplastic syndrome (MDS)[37] is associated with acquired haplo-insufficiency of RPS14,[38] a component of the eukaryotic small ribosomal subunit (40S).[5] RPS14 is critical for 40S assembly, and depletion of RPS14 in human CD34(+) cells is sufficient to recapitulate the 5q- defect of erythropoiesis with sparing of megakaryocytes.[5]

Treacher Collins syndrome[edit]

Treacher Collins syndrome (TCS)

Cartilage–hair hypoplasia[edit]

Cartilage–hair hypoplasia (CHH) - some sources list confidently as ribosomopathy, others question[citation needed]

North American Indian childhood cirrhosis[edit]

NAIC is an autosomal recessive abnormality of the CIRH1A gene, which codes for cirhin. Neonatal jaundice advances over time to biliary cirrhosis with severe liver fibrosis.

Isolated congenital asplenia[edit]

Bowen–Conradi syndrome[edit]

Bowen–Conradi syndrome (BCS[39] or BWCNS[40]) is an autosomal recessive abnormality of the EMG1 gene, which plays a role in small ribosomal subunit (SSU) assembly.[39][41][42] Most affected children have been from North American Hutterite families, but BWCNS can affect other population groups.[40][43] Skeletal dysmorphology is seen[40][43] and severe prenatal and postnatal growth failure usually leads to death by one year of age.[44]


Familial colorectal cancer type X[edit]

Unlike the mutations of the 5 genes associated with DNA mismatch repair, which are associated with Lynch syndrome with hereditary nonpolyposis colorectal cancer (HNPCC) due to microsatellite instability, familial colorectal cancer (CRC) type X (FCCX) gives rise to HNPCC despite microsatellite stability.[45] FCCX is most likely etiologically heterogeneous but RPS20 may be implicated in some cases.[45]


The p53 pathway is central to the ribosomopathy phenotype.[46] Ribosomal stress triggers activation of the p53 signaling pathway.[47][48]


Cancer cells have irregularly shaped, large nucleoli, which may correspond ribosomal gene transcription up-regulation, and hence high cell proliferation. Oncogenes, like c-Myc, can upregulate rDNA transcription in a direct and indirect fashion. Tumor suppressors like Rb and p53, on the other hand, can suppress ribosome biogenesis. Additionally, the nucleolus is an important cellular sensor for stress and plays a key role in the activation of p53.

Ribosomopathy has been linked to the pathology of various malignancies.[46] Several ribosomopathies are associated with an increased rate of cancer. For example, both SDS and 5q- syndrome lead to impaired hematopoiesis and a predisposition to leukemia.[37] Additionally, acquired defects in ribosomal proteins that have not been implicated in congenital ribosomopathies have been found in T-lymphoblastic leukemia/lymphoma, stomach cancer and ovarian cancer.[3]

New cancer therapies might therefore target ribosome biogenesis specifically. As of 2014, two experimental agents inhibit RNA polymerase I by disrupting the rDNA promoter complex: CX-5461 activates p53 via nuclear stress and induces apoptosis of leukemia and lymphoma cells while leaving normal cells unharmed; BMH-21, inhibits rDNA transcription and induces nucleolar capping or nucleolar reorganization. This nucleolar stress eventually causes decreased cell proliferation and death. It also activates p-53 but p-53 activation was not required for the drug to be effective. The promise of these drugs is that they leave healthy cell DNA unharmed and specifically target the fact that cancer cells rely heavily on ribosome biogenesis. It has been said that ribosome biogenesis is the “Achilles heel in cancer cells.” [49]


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