Ribosomopathy


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.

Ribosomes

s are essential for protein synthesis in all living organisms. Prokaryotic and eukaryotic ribosomes both contain a of ribosomal RNA on which are arrayed an extensive variety of ribosomal proteins. 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 and a small 40S subunit.
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 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 and 5.8S, and via 30S to 18S, as shown in the diagram. 18S is a component of the ribosomal 40S subunit. 28S, 5.8S and 5S, which is transcribed independently, are components of 60S. The 5S DNA occurs in tandem arrays ; the largest is on chromosome 1q41-42. 5S rRNA is transcribed by RNA polymerase III. 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. and 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. 60S rRNA acts as a ribozyme, catalyzing peptide bond formation, while 40S monitors the complementarity between tRNA anticodon and mRNA.

Diseases

Abnormal ribosome biogenesis is linked to several human genetic diseases.
Ribosomopathy has been linked to skeletal muscle atrophy, and underpins most Diamond–Blackfan anemia, the X-linked subtype of dyskeratosis congenita, Treacher Collins syndrome , Shwachman–Diamond syndrome and 5q- myelodysplastic syndrome., North American Indian childhood cirrhosis, isolated congenital asplenia, and Bowen–Conradi syndrome, CHARGE syndrome and ANE syndrome.
The associated chromosome, OMIM genotype, phenotype, and possible disruption points are shown:
namechromosomegenotypephenotype proteindisruption
DBA119q13.2RPS1930S to 18S
DBA28p23-p22unknown
DBA310q22-q23RPS2430S to 18S
DBA415qRPS1730S to 18S
DBA53q29-qterRPL35A32S to 5.8S/28S
DBA61p22.1RPL532S to 5.8S/28S
DBA71p36.1-p35RPL1132S to 5.8S/28S
DBA82p25RPS730S to 18S
DBA96pRPS1030S to 18S
DBA1012qRPS2630S to 18S
DBA1117p13RPS2630S to 18S
DBA123p24RPL1545S to 32S
DBA1314qRPS29
DKCXXq28dyskerinassociated with both H/ACA small nucleolar RNA and with the RNA component of TERC
TCS
5q-5q33.1RPS1430S to 18S
SDS7q11.21SBDS60S to 80S
CHH9p13.3RMRPmitochondrial RNA processing
NAIC16q22.1cirhinpartial loss of interaction between cirhin and NOL11
ICAS3p22.1RPSA
BWCNS12p13.31EMG118S to 40S
CHARGE8q12.1-q12.2; also 7q21.11CHD7; also SEMA3E
ACESRBM28

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. Other features can include skeletal abnormalities and growth retardation. However, clinically these diseases are distinct, and do not show a consistent set of features.

Diamond–Blackfan anemia

With the exception of rare GATA1 genotypes, Diamond–Blackfan anemia arises from a variety of mutations that cause ribosomopathies.

Dyskeratosis congenita

The X-linked subtype of dyskeratosis congenita

Shwachman–Diamond syndrome

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. Clinically, SDS affects multiple systems, causing bony abnormalities, and pancreatic and neurocognitive dysfunction. 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

is associated with acquired haplo-insufficiency of RPS14, a component of the eukaryotic small ribosomal subunit. 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.

Treacher Collins syndrome

Cartilage–hair hypoplasia

- some sources list confidently as ribosomopathy, others question

North American Indian childhood cirrhosis

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

Bowen–Conradi syndrome

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

Other

Familial colorectal cancer type X

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

p53

The p53 pathway is central to the ribosomopathy phenotype. Ribosomal stress triggers activation of the p53 signaling pathway.

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. 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. 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.
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.”