Ribosomopathies are diseases caused by abnormalities in the structure or function of

ribosomal Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to for ...

component

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s or

rRNA 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 ribosoma ...

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

s, or other genes whose products are involved in

ribosome biogenesis 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. I ...

Ribosomes

Ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...

s are essential for

protein synthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the product ...

in all living organisms.

Prokaryotic A prokaryote () is a Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...

and

eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

ribosomes both contain a

scaffold Scaffolding, also called scaffold or staging, is a temporary structure used to support a work crew and materials to aid in the construction, maintenance and repair of buildings, bridges and all other man-made structures. Scaffolds are widely used ...

ribosomal RNA 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 ...

(rRNA) on which are arrayed an extensive variety of

ribosomal protein A ribosomal protein (r-protein or rProtein) is any of the proteins that, in conjunction with rRNA, make up the ribosomal subunits involved in the cellular process of translation. ''E. coli'', other bacteria and Archaea have a 30S small subunit an ...

s (RP). 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 An ultracentrifuge is a centrifuge optimized for spinning a rotor at very high speeds, capable of generating acceleration as high as (approx. ). There are two kinds of ultracentrifuges, the preparative and the analytical ultracentrifuge. Both cla ...

sedimentation coefficient The sedimentation coefficient () of a particle characterizes its sedimentation during centrifugation. It is defined as the ratio of a particle's sedimentation velocity to the applied acceleration causing the sedimentation. : s = \frac The sedime ...

, 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). 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 The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of sig ...

RNA polymerase I RNA polymerase 1 (also known as Pol I) is, in higher eukaryotes, the polymerase that only transcribes ribosomal RNA (but not 5S rRNA, which is synthesized by RNA polymerase III), a type of RNA that accounts for over 50% of the total RNA synthesiz ...

. 45S is processed in the nucleus via 32S rRNA to

28S 28S ribosomal RNA is the structural ribosomal RNA (rRNA) for the LSU rRNA, large subunit (LSU) of eukaryotic cytoplasmic ribosomes, and thus one of the basic components of all eukaryotic cells. It has a size of 25S in plants and 28S in mammals, ...

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 (~200-300 true 5S genes and many dispersed

pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by DNA duplication or indirectly by Reverse transcriptase, reverse transcription of an mRNA trans ...

s); the largest is on chromosome 1q41-42. 5S rRNA is transcribed by

RNA polymerase III In eukaryote cells, RNA polymerase III (also called Pol III) is a protein that transcribes DNA to synthesize ribosomal 5S rRNA, tRNA and other small RNAs. The genes transcribed by RNA Pol III fall in the category of "housekeeping" genes whose e ...

. 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 The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...

are the four principal types of cytoplasmic rRNA: 28S, 5.8S, 18S, and 5S subunits. 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

in mammals, 25S in plants). 60S rRNA acts as a

ribozyme Ribozymes (ribonucleic acid enzymes) are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozymes demonst ...

, catalyzing peptide bond formation, while 40S monitors the complementarity between

tRNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...

anticodon Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...

and

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

Diseases

Abnormal

is linked to several human

genetic diseases A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

. Ribosomopathy has been linked to skeletal muscle atrophy, and underpins most

Diamond–Blackfan anemia 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 (the platelets and the white blood cel ...

(DBA), the

X-linked Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...

subtype of

dyskeratosis congenita 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 ...

(DKCX),

Treacher Collins syndrome Treacher Collins syndrome (TCS) is a genetic disorder characterized by deformities of the ears, eyes, cheekbones, and chin. The degree to which a person is affected, however, may vary from mild to severe. Complications may include breathing prob ...

(TCS),

Shwachman–Diamond syndrome Shwachman–Diamond syndrome (SDS), or Shwachman–Bodian–Diamond syndrome, is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities and short stature. After cystic fib ...

(SDS) and 5q-

myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...

.(5q- MDS),(cite)(cite)

North American Indian childhood cirrhosis 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. ...

(NAIC), isolated congenital asplenia (ICAS), and Bowen–Conradi syndrome (BWCNS),

CHARGE syndrome CHARGE syndrome (formerly known as CHARGE association) is a rare syndrome caused by a genetic disorder. First described in 1979, the acronym "CHARGE" came into use for newborn children with the congenital features of coloboma of the eye, heart ...

and ANE syndrome (ANES). The associated

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

OMIM Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship. , approximately 9,000 of the over 25,000 entries in OMIM r ...

genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

, and possible disruption points are shown: 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 Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. 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 GATA-binding factor 1 or GATA-1 (also termed Erythroid transcription factor) is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by ...

genotypes,(cite)

(DBA) arises from a variety of mutations that cause ribosomopathies.

Dyskeratosis congenita

The

subtype of

(DKCX)

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 Eukaryotic translation initiation factor 6 (EIF6), also known as Integrin beta 4 binding protein (ITGB4BP), is a human gene. Hemidesmosomes are structures which link the basal lamina to the intermediate filament cytoskeleton. An important functio ...

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

5q-

(MDS) is associated with acquired haplo-insufficiency of RPS14, a component of the

eukaryotic small ribosomal subunit (40S) The eukaryotic small ribosomal subunit (40S) is the smaller subunit of the eukaryotic 80S ribosomes, with the other major component being the large ribosomal subunit (60S). The "40S" and "60S" names originate from the convention that ribosomal pa ...

. RPS14 is critical for 40S assembly, and depletion of RPS14 in human

CD34 CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species. CD34 derives its name from the cluster of differentiation protocol that identifies cell surface antigens. CD34 was first descri ...

(+) cells is sufficient to recapitulate the 5q- defect of

erythropoiesis Erythropoiesis (from Greek 'erythro' meaning "red" and 'poiesis' "to make") is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell. It is stimulated by decrea ...

with sparing of

megakaryocytes A megakaryocyte (''mega-'' + '' karyo-'' + '' -cyte'', "large-nucleus cell") is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In hum ...

Treacher Collins syndrome

(TCS)

Cartilage–hair hypoplasia

Cartilage–hair hypoplasia Cartilage–hair hypoplasia (CHH) is a rare genetic disorder. Symptoms may include short-limbed dwarfism due to skeletal dysplasia, variable level of immunodeficiency, and predisposition to cancer. It was first reported by Victor McKusick in 1965 ...

(CHH) - some sources list confidently as ribosomopathy, others question

North American Indian childhood cirrhosis

NAIC is an autosomal recessive abnormality of the '' UTP4'' gene, which codes for cirhin.

Neonatal jaundice Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral pals ...

advances over time to biliary

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...

with severe liver

fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...

Isolated congenital asplenia

Bowen–Conradi syndrome

Bowen–Conradi syndrome (BCS or BWCNS) is an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

abnormality of the '' EMG1''

, which plays a role in small ribosomal subunit (SSU) assembly. Most affected children have been from North American

Hutterite Hutterites (german: link=no, Hutterer), also called Hutterian Brethren (German: ), are a communal ethnoreligious group, ethnoreligious branch of Anabaptism, Anabaptists, who, like the Amish and Mennonites, trace their roots to the Radical Refor ...

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 DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of nucleobase, bases that can arise during DNA replication and Genetic recombination, recombination, as well as DNA repair, r ...

, which are associated with

Lynch syndrome Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is an autosomal dominant genetic condition that is associated with a high risk of colon cancer as well as other cancers including endometrial cancer (second most common), ovary, ...

with hereditary nonpolyposis colorectal cancer (HNPCC) due to

microsatellite instability Microsatellite instability (MSI) is the condition of genetic hypermutability (predisposition to mutation) that results from impaired DNA mismatch repair (MMR). The presence of MSI represents phenotypic evidence that MMR is not functioning normal ...

, familial colorectal cancer (CRC) type X (FCCX) gives rise to HNPCC despite microsatellite stability. FCCX is most likely etiologically heterogeneous but

RPS20 40S ribosomal protein S20 is a protein that in humans is encoded by the ''RPS20'' gene. Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 ...

may be implicated in some cases.

p53

The

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

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

Cancer

Cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

cells have irregularly shaped, large

nucleoli The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of s ...

, which may correspond ribosomal gene transcription up-regulation, and hence high

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...

Oncogenes An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

, like

c-Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...

, can upregulate rDNA transcription in a direct and indirect fashion. Tumor suppressors like Rb and

, 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 Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...

and a predisposition to

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...

. Additionally, acquired defects in ribosomal proteins that have not been implicated in congenital ribosomopathies have been found in

T-lymphoblastic leukemia/lymphoma T-lymphoblastic leukemia/lymphoma (WHO 2008), previously labeled precursor T-lymphoblastic leukemia/lymphoma (WHO 2001) is a form of lymphoid leukemia and lymphoma in which too many T-cell lymphoblasts (immature white blood cells) are found in the ...

stomach cancer Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...

and

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...

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OMIM entry 105650: Diamond-Blackfan anemia. Johns Hopkins University

/ref> Online Mendelian Inheritance in Man. OMIM entry 150370: Ribosomal protein SA; RPSA. Johns Hopkins University

/ref> Online Mendelian Inheritance in Man. OMIM entry 211180: XXX. Johns Hopkins University

/ref> Online Mendelian Inheritance in Man. OMIM entry 271400: Asplenia, isolated congenital; ICAS. Johns Hopkins University

/ref> Online Mendelian Inheritance in Man. OMIM entry 305000: Dyskeratosis congenita, X–linked; DKCX. Johns Hopkins University

/ref> Online Mendelian Inheritance in Man. OMIM entry 603632: Ribosomal protein S10; RPS10. Johns Hopkins University

/ref> Online Mendelian Inheritance in Man. OMIM entry 603701: Ribosomal protein S26; RPS26. Johns Hopkins University

/ref> Online Mendelian Inheritance in Man. OMIM entry 604174: Ribosomal protein L15; RPL15. Johns Hopkins University

/ref> Online Mendelian Inheritance in Man. OMIM entry 611531: Essential for mitotic growth 1, S. cervevisiae, Homolog of; EMG1. Johns Hopkins University

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