2. RNA Genes And Ribosomopathies Flashcards
MicroRNAs
Small RNA molecules 21-23 nucleotides that participate in gene regulation by RNA interference
By binding miRNA inhibits translation or degrades mRNA - gene silencing
Pri-miRNA - pre-miRNA - DICER mature miRNA
Anti-miR 155 - over expressed (hematological cancer)
MiR34 - liver cancer
Long ncRNAs
Greater then 200 nucleotides long
Functions:
regulation of allelic expression (X chromosome inactivation, imprinting)
Development (lineage commitment myogenesis ) with disease states (cancer, Muscular dystrophy, heart failure)
Human Genome Project
Obtained the complete DNA suqence in human nuclear genome
Not all regions were sequenced
High priority: DNA or euchromatin (transcriptionally active) 93%
Low priority - DNA of heterochromatin (transcriptionally inactive / non coding) 7%
Encyclopedia of DNA elements (ENCODE)
Aims to identify functional elements of human genome
Launched by the US national human genome research insitute (NHGRI) in September 2003
Primary goal: to determine the role of the remaining component of the genome, much of which was traditionally regarded as “junk”
Tandem Repeats
Over two-thirds of the sequence in the human genome consists of repetitive elements
Functional multi copy genes - actin, tubular
RS with uncertain functions - minisatellites, microsatellites (do not know function)
Huntington’s Disease - CAG repeats fragile X syndrome, spinocerebellar ataxia, myotonic dystrophy and Fredrick ataxia
Transplants
Mobile DNA elements that were able to migrate from one location in the genome to another
Insert in wrong place can cause mutation
Ribosompathies
Congenital and acquired bone marrow failure have been linked to molecular defects in ribosomal biogenesis
Teacher Collins syndrome
Diamond black fan anemia
5q-syndrome
Dyskeratosis congenita
Cartilage hair hyperplasia syndrome
Schwachman-diamond syndrome
How mutation in a ribosomal protein can lead to such selective defects
Ribosomal halploinsufficency -
distrubted ribosome biogenesis -
accumulation oof free ribosomal proteins -
binds MDM2 (p53 repressor) -activated p53-
apoptosis and cell cycle arrest - anemia
Relative excess free heme - erythropoietin specific apoptosis - anemia
Bone marrow failure - increased risk of cancer and developmental disorders
Bone marrow is more sensitive to p53 - cause cell cycle arrest
Leukemia
MrRNA over expression
Dysregulation of cell cycle associated genes
Leukemia
MiR-17-92 is over expressed in b-cell lymphomas, acute lymphoid and myeloid leukemia’s
Over-expression causes cells to be more primitive - stem cells give rise to cancer
Hemophilia
Transposons - insertional mutagenesis
Hemophilia A - clotting disorder due to factor VIII deficiency - blood less likely to clot
Transposin insertion
Mutation in factor VIII gene
Hemophilia
Excess bleeding
Other conditions related to transposable elements - neurofibromatosis and breast/ovarian cancer due to mutation of BRCA gene
Peripheral neuropathies
Mutations in tRNA produce problems with tRNA synthesis and coupling
Disease-causing mutations only found in mitochondrial tRNA
Charcot-Marie-tooth- disease
One of the most common inherited sensory and motor neuropathy - nerve damage mostly in arms and legs
Other examples: alzheimer disease, Parkinson’s disease, atherosclerosis
TRNA mutations - defects in neuronal proteins - myelin sheath or atonal damage
Charcot-Marie-tooth-disease
Peripheral neuropathy
Signs/symptoms
Loss of muscle bulk and weakness in legs, ankles, feet
Curled toes (hammertoes)
Decrease ability to run
Foot drop, gait change
Frequent tripping or falling
Decrease sensation or loss of feeling in legs and feet
Huntington disease
Autosomal dominant neurodegenerative condition caused by mutations in the gene Huntington (increase CAG repeats)
Characterized by adult onset degeneration of basal ganglia - progressive neurological symptoms that include involuntary and abnormal (choreiform) movements (Huntington’s chorea)
Symptoms noticeable between 35-45
Progressive neurological problems result in early death
Diamond blackjack anemia
Ribosomopathies - pedigree difficultdue to variable penetrate of disease manifestations
Presents in the first year with hypoproductive anemia, often with macrocytosis
Bone marrow: normocellualr marrow with reduced erythrocytes precursors
Increase HbF EPO erythrocytes ADA
Nonhaematological features:
Short stature, craniofacial, skeletal and urogenital anomalies
Increase incidence of acute
AML and osteogenic sarcoma
Mutations in RPS19 and RPS24- impair pre-rRNA processing of the 18S rRNA
Decrease production of 40S ribosomal subunit
5q minus syndrome
Ribsomopathies
Refractory anemia and interstitial deletion of 5q - block erthyoid differentiation
Somatic mutation after conception - No F/H
Severe macrocytic anemia
Normal/elevated platelets with hypolobulated micromegakaryocytes
Relatively low rate of progression to AML
Lenalidomide :
Increase eyrthropoiesus, modulation of cytokines production, inhibition of phosphates
RPS14 - decrease 40S ribosomes - decrease erythropoeisis
5q32-q33 - SPARC, RPS14 and several miRNA genes
