Ribosomopathy

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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]

Contents

Ribosomes

Ribosomal rRNA subunits Ribosomal rRNA subunits.png
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.[ citation needed ]

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.[ citation needed ]

Diseases

Abnormal ribosome biogenesis is linked to several human genetic diseases.[ citation needed ]

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:

Ribosomopathies
namechromosomegenotype [25] phenotype proteindisruption(cite)(cite)
DBA1 [25] 19q13.2 603474 105650 RPS19 30S to 18S [10] : 291 (cite)
DBA28p23-p22unknown 606129
DBA310q22-q23 602412 610629 RPS24 [26] 30S to 18S [10] : 291 (cite)
DBA415q 180472 612527 RPS17 [27] 30S to 18S [10] : 291 
DBA53q29-qter 180468 612528 RPL35A [28] 32S to 5.8S/28S [10] : 291 (cite)
DBA61p22.1 603634 612561 RPL5 [29] 32S to 5.8S/28S [10] : 291 
DBA71p36.1-p35 604175 612562 RPL11 [29] 32S to 5.8S/28S [10] : 291 
DBA82p25 603658 612563 RPS7 [29] 30S to 18S [10] : 291 
DBA96p 603632 613308 RPS10 [25] 30S to 18S [30]
DBA1012q 603701 613309 RPS26 30S to 18S [31]
DBA1117p13 603704 614900 RPS26 30S to 18S [31]
DBA123p24 604174 615550 RPL15 45S to 32S [32]
DBA1314q 603633 615909 RPS29
DKCXXq28 300126 305000 dyskerin associated with both H/ACA small nucleolar RNA (snoRNA) and with the RNA component of TERC [33]
TCS
5q-5q33.1 130620 153550 RPS14 30S to 18S [10] : 291 
SDS7q11.21 607444 260400 SBDS 60S to 80S [10] : 291 
CHH9p13.3 157660 250250 RMRP mitochondrial RNA processing
NAIC16q22.1 607456 604901 cirhin partial loss of interaction between cirhin and NOL11 [34]
ICAS3p22.1 150370 271400 RPSA
BWCNS12p13.31 611531 211180 EMG1 18S to 40S
CHARGE8q12.1-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

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

Dyskeratosis congenita

The X-linked subtype of dyskeratosis congenita (DKCX)[ citation needed ]

Shwachman–Diamond syndrome

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.[ citation needed ]

5q- myelodysplastic syndrome

5q- myelodysplastic syndrome (MDS) [37] is associated with acquired haplo-insufficiency of RPS14, [37] 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

Treacher Collins syndrome (TCS)

Cartilage–hair hypoplasia

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

North American Indian childhood cirrhosis

NAIC is an autosomal recessive abnormality of the UTP4 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 (BCS [38] or BWCNS [39] ) is an autosomal recessive abnormality of the EMG1 gene, which plays a role in small ribosomal subunit (SSU) assembly. [38] [40] [41] Most affected children have been from North American Hutterite families, but BWCNS can affect other population groups. [39] [42] Skeletal dysmorphology is seen [39] [42] and severe prenatal and postnatal growth failure usually leads to death by one year of age. [43]

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 (HNPCC) due to microsatellite instability, familial colorectal cancer (CRC) type X (FCCX) gives rise to HNPCC despite microsatellite stability. [44] FCCX is most likely etiologically heterogeneous but RPS20 may be implicated in some cases. [44]

p53

The p53 pathway is central to the ribosomopathy phenotype. [45] Ribosomal stress triggers activation of the p53 signaling pathway. [46] [47]

Cancer

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. [45] 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]

Related Research Articles

<span class="mw-page-title-main">Fanconi anemia</span> Medical condition

Fanconi anemia (FA) is a rare, AR, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), MDS, and liver tumors. 90% develop aplastic anemia by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has later onset bone marrow failure.

<span class="mw-page-title-main">Chromosome 5q deletion syndrome</span> Human disease

Chromosome 5q deletion syndrome is an acquired, hematological disorder characterized by loss of part of the long arm of human chromosome 5 in bone marrow myelocyte cells. This chromosome abnormality is most commonly associated with the myelodysplastic syndrome.

<span class="mw-page-title-main">Ribosomal RNA</span> RNA component of the ribosome, essential for protein synthesis in all living organisms

Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal DNA (rDNA) and then bound to ribosomal proteins to form small and large ribosome subunits. rRNA is the physical and mechanical factor of the ribosome that forces transfer RNA (tRNA) and messenger RNA (mRNA) to process and translate the latter into proteins. Ribosomal RNA is the predominant form of RNA found in most cells; it makes up about 80% of cellular RNA despite never being translated into proteins itself. Ribosomes are composed of approximately 60% rRNA and 40% ribosomal proteins by mass.

Diamond–Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy. DBA causes low red blood cell counts (anemia), without substantially affecting the other blood components, which are usually normal. This is in contrast to Shwachman–Bodian–Diamond syndrome, in which the bone marrow defect results primarily in neutropenia, and Fanconi anemia, where all cell lines are affected resulting in pancytopenia. There is a risk to develop acute myelogenous leukemia (AML) and certain other cancers.

<span class="mw-page-title-main">Dyskeratosis congenita</span> Medical condition

Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa, and MDS/AML, but these components do not always occur. DKC is characterized by short telomeres. Some of the manifestations resemble premature ageing and cognitive impairment can be a feature. The disease initially mainly affects the skin, but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality.

<span class="mw-page-title-main">Ribosome biogenesis</span> Cellular process

Ribosome biogenesis is the process of making ribosomes. In prokaryotes, this process takes place in the cytoplasm with the transcription of many ribosome gene operons. In eukaryotes, it takes place both in the cytoplasm and in the nucleolus. It involves the coordinated function of over 200 proteins in the synthesis and processing of the three prokaryotic or four eukaryotic rRNAs, as well as assembly of those rRNAs with the ribosomal proteins. Most of the ribosomal proteins fall into various energy-consuming enzyme families including ATP-dependent RNA helicases, AAA-ATPases, GTPases, and kinases. About 60% of a cell's energy is spent on ribosome production and maintenance.

<span class="mw-page-title-main">60S ribosomal protein L5</span> Protein found in humans

60S ribosomal protein L5 is a protein that in humans is encoded by the RPL5 gene.

<span class="mw-page-title-main">40S ribosomal protein S19</span> Protein-coding gene in the species Homo sapiens

40S ribosomal protein S19 is a protein that in humans is encoded by the RPS19 gene.

<span class="mw-page-title-main">60S ribosomal protein L11</span> Protein found in humans

60S ribosomal protein L11 is a protein that in humans is encoded by the RPL11 gene.

<span class="mw-page-title-main">40S ribosomal protein S10</span> Protein-coding gene in the species Homo sapiens

40S ribosomal protein S10 is a protein that in humans is encoded by the RPS10 gene.

<span class="mw-page-title-main">SBDS</span> Protein-coding gene in the species Homo sapiens

Ribosome maturation protein SBDS is a protein that in humans is encoded by the SBDS gene. An alternative transcript has been described, but its biological nature has not been determined. This gene has a closely linked pseudogene that is distally located. This gene encodes a member of a highly conserved protein family that exists from archaea to vertebrates and plants.

<span class="mw-page-title-main">40S ribosomal protein S29</span> Protein-coding gene in the species Homo sapiens

40S ribosomal protein S29 is a protein that in humans is encoded by the RPS29 gene.

<span class="mw-page-title-main">Mitochondrial ribosomal protein L11</span> Protein-coding gene in the species Homo sapiens

39S ribosomal protein L11, mitochondrial is a protein that in humans is encoded by the MRPL11 gene.

<span class="mw-page-title-main">Mitochondrial ribosomal protein L39</span> Protein-coding gene in the species Homo sapiens

39S ribosomal protein L39, mitochondrial is a protein that in humans is encoded by the MRPL39 gene.

Congenital hypoplastic anemia is a congenital disorder that occasionally also includes leukopenia and thrombocytopenia and is characterized by deficiencies of red cell precursors.

<span class="mw-page-title-main">Eukaryotic ribosome</span> Large and complex molecular machine

Ribosomes are a large and complex molecular machine that catalyzes the synthesis of proteins, referred to as translation. The ribosome selects aminoacylated transfer RNAs (tRNAs) based on the sequence of a protein-encoding messenger RNA (mRNA) and covalently links the amino acids into a polypeptide chain. Ribosomes from all organisms share a highly conserved catalytic center. However, the ribosomes of eukaryotes are much larger than prokaryotic ribosomes and subject to more complex regulation and biogenesis pathways. Eukaryotic ribosomes are also known as 80S ribosomes, referring to their sedimentation coefficients in Svedberg units, because they sediment faster than the prokaryotic (70S) ribosomes. Eukaryotic ribosomes have two unequal subunits, designated small subunit (40S) and large subunit (60S) according to their sedimentation coefficients. Both subunits contain dozens of ribosomal proteins arranged on a scaffold composed of ribosomal RNA (rRNA). The small subunit monitors the complementarity between tRNA anticodon and mRNA, while the large subunit catalyzes peptide bond formation.

<span class="mw-page-title-main">Shwachman–Diamond syndrome</span> Medical condition

Shwachman–Diamond syndrome (SDS), or Shwachman–Bodian–Diamond syndrome, is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal and cardiac abnormalities and short stature. After cystic fibrosis (CF), it is the second most common cause of exocrine pancreatic insufficiency in children. It is associated with the SBDS gene and has autosomal recessive inheritance.

North American Indian childhood cirrhosis (NAIC) is a disease in humans that can affect Ojibway-Cree children in northwestern Quebec, Canada. The disease is due to an autosomal recessive abnormality of the UTP4 gene, which codes for cirhin, a nucleolar protein.

Bowen–Conradi syndrome is a disease in humans that can affect children. The disease is due to an autosomal recessive abnormality of the EMG1 gene, which plays a role in small ribosomal subunit (SSU) assembly. The preponderance of diagnoses has been in North American Hutterite children, but BWCNS can affect other population groups.

<span class="mw-page-title-main">Mitochondrial ribosome</span> Protein complex

The mitochondrial ribosome, or mitoribosome, is a protein complex that is active in mitochondria and functions as a riboprotein for translating mitochondrial mRNAs encoded in mtDNA. The mitoribosome is attached to the inner mitochondrial membrane. Mitoribosomes, like cytoplasmic ribosomes, consist of two subunits — large (mt-LSU) and small (mt-SSU). Mitoribosomes consist of several specific proteins and fewer rRNAs. While mitochondrial rRNAs are encoded in the mitochondrial genome, the proteins that make up mitoribosomes are encoded in the nucleus and assembled by cytoplasmic ribosomes before being implanted into the mitochondria.

References

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  24. ↑ 612079
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  33. ↑ 300126
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