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Embed code for: Syndromes of telomere shrotening
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BASIC UNDERSTANDING & PATHOGENESIS
The human genome
It is estimated that there are up to 150k genes
Human genome is 50% represented by repetitive sequences
Noncoding unique sequences
98% of the human genome represents noncoding dna
Were discoverede in persuit of questions about how the ends of the chromosomes are maintained
Their implication in age-related disease have emerged in recent years with the recognition of a group of telomere-mediated syndromes.
They represent DNA-protein structures that protect the chromosomes’ ends
Telomeres consist of TTAGGG repeats who are bound together and protected by SHELTERIN
THE END REPLICATION PROBLEM & TELOMERES
Critically short telomeres recruit DNA damage proteins that activarte scenescence or apoptosis through the p53 dependent checkpoint
Telomerase biogenesis requires the assembly of two main components:
TELOMERASE REVERSETRANSCRIPTASE (hTERT) a catalytic component
TELOMERASE RNA (hTR) a template
a telomerase b shelterine
Telomere genetics are unique
The study of the telomerase knockout mouse has provided key insights into the pathophysiology of telomere-mediated disease
The most proeminent manifestations are in tissues of high turnover
The shortest telomere has a genetically dominant effect and is sufficient to induce a DNA-damage response, which brings an aditional variable to the fenotype heterogenity
Individuals who inherit the shortest telomeres as well as a mutation may have more pronounced phenotypes than individuals who inherit long telomeres and a mutation
Short telomeres, even in the presence of telomerase, limit tissue renewal capacity
Short telomeres can be both inherited and aquired
inherited across generations, the progressive telomere shortening leads to “anticipation “
mutations in hTR and hTERT lead to haploinsufficiency of telomerase and affected families display genetic anticipation, an earlier and more severe onset of phenotypes with successive generations
severity depends on which generation is examined
as adult-onset pulmonary fibrosis
Aplastic anemia or DC
Telomere length is a mosaic trait and reflects the replicative history of cells
Chronic injury-repair disease states are also associated with telomere shortening for exemple:
chronic exposure to cigarette smoke in the lung, acid reflux in Barrett’s esophagus, chronic inflammatory processes such as in ulcerative colitis
Additionally, telomere shortening can be observed as a consequence of infection
Implication for cell cancer
Several lines of evidence suggest that shortened telomeres contribute to the initiation and progression of malignant tumors in several ways
Chromosomes that lack protective telomeric structure are highly unstable,being subject of degradation, rearrangement or fusion, patterns usually found in neoplasic cells
They try to stabilise by producing telomarese
Telomeres and cancer
Cells escape death by producing an abnormal ammount of telomerase enzyme, which prevents the telomeres from getting even shorter
This way, cells will not activate the damage proteins thus they will be “immortal”
Combined with mutations that promote cell growth
They will keep dividing uncontrolably
Cancer treatment by
stopping telomerase activity
Using telomerase high activity as a tumoral marker
Mass produced stem cells and genetically improved organisms
Telomeres the key to aging
Telomere dysfunction contributes to aging by its ability to induce cellular senescence which affects their metabolism.
Cells start to secrete factors that may contribute to the decline of tissue function and integrity, representing a hallmark of aging
prospects of extending cell lifespan
Possitive results in vitro
Researchers have been able to use telomerase to keep human cells dividing far beyond their normal limit, and the cells did not become cancerous.
In vivo, due to interaction with teratogenic factors as well as the pressence of other proaging processes, concrete results are yet to come
In a ground-breaking 2012 paper by Bruno Bernardes de Jesus, ordinary lab mice were given gene therapy with an “extra” telomerase gene spread to their cells by a genetically-engineered virus and the mice lived 13-24% longer
The main syndromes of telomere shortening
Syndromes of telomere shortening are clinically resembling dissease manifested in ealderly people such as:
Bone marrow aplasia
High turnover tissue dysfunction
High blood pressure
The spectrum of telomere-mediated disease is broad and includes clinical presentations in both children and adults.
Initially only children with majour clinical manifestations were diagnosed , but by studying several cluster families more dissease were added to the spectrum of telomere shortening
Telomere-mediated disease which was initially identified in the context of a rare syndrome of premature aging.
Initially recognized by clinicians as a triad of mucocutaneous features that they noted in male children: oral leukoplakia, skin hyperpigmentation, and nail dystrophy, all associated with premature mortality due to bone marrow failure in aplastic anemia .
At first, it was belived that DC is a Xlinked disease in which patients had lower levels of telomerase RNA and short telomeres due to DKC1 mutations
Mutations in NOP10 and NHP2, proteins asociated with the dyskerin complex, have also been identified in rare autosomal recessive families
Recently, heterozygous mutations in the shelterin component TINF2, were identified in severe cases of DC
The severity of dyskeratosis congenita varies widely among affected individuals.
It can vary from mild mucocutaneous manifestations, to progressive aplastic anemia, severe immunodeficiency, and cerebellar hypoplasia .
Some of these manifestatios alone can be a presentation of a telomere syndrome themselves
Reprsents the prototype of stem cell failure disorders. Patients with familial aplastic anemia and constitutional aplastic anemia, ~5%, also carry mutations in either hTR or hTERT.
Aplastic anemia is a likely a marker of more severe phenotypes in individuals with mutant telomerase.
In a family, mutation carriers who present first with aplastic anemia are generally up to two decades younger than those who present with IPF.
IDIOPATHIC PULMONARY FIBROSIS (IPF)
A subset of idiopathic pulmonary fibrosis patients falls on the spectrum of telomere syndromes, IPF being the most common manifestation of a syndrome of telomere shortening
In a study of a specific family, it was noted that in addition to anticipation of the aplastic anemia phenotype, pulmonary fibrosis and liver disease manifested earlier and more severely with each generation
hTR and hTERT may be candidate genes in familial IPF where the inheritance is also known to be autosomal dominant
organ failure in the bone marrow, lung, and liver
Organ failure seems idiopathic and is often mistaken for an autoimmune process, although it does not respond to immunosuppression. The poor response to immunosuppression has been best documented in aplastic anemia and IPF.
Overall the criteria for telomere shortening sindrome are constantly changing due to the incomplete understanding of their pathogenesis.
It is proposed that these three features are sufficient to define a syndrome of telomere shortening in individuals and families who lack the classic DC features.
lomere dysfunction contributes to aging by its ability to induce cellular senescence which affects their metabolism.
In vivo, due to interaction with teratogenic factors as well as the pres