TBL 1 Flashcards
Sickle Cell Anemia exhibits _____ inheritance
autosomal recessive
Sickle Cell Anemia Inheritance: Normal father + father trait (heterozygous) yields
normal children and/or children with the trait
Since sickle cell anemia is autosomal recessive the disorder will only occur in individuals who are ____ for the sickle cells trait
Homozygous recessive
A father with sickle cell anemia + a mother with sickle anemia yields ____
only children with sickle cell anemia
One way for sickle cell anemia to occur for an individual’s parents to both be ___ for the sickle cell trait
heterozygous
A mother with trait (heterozygous) + a father with trait (heterozygous) yields ____
children with trait, normal children, and/or children with sickle cell anemia
There is ___ chance that two parents who are heterozygous for sickle cell anemia would produce a homozygous recessive offspring
25%
A mother with trait (heterozygous) + a father with sickle cell anemia yields ___ and/or ___.
children with trait; children with sickle cell anemia
There is a ___ chance that two parents who are heterozygous for sickle cell anemia would produce a child that would be heterozygous “carrier” or someone who has the trait but does not know
50%
A father with sickle cell anemia + a normal mother yields ____
only children with the trait
The gene that causes Sickle Cell Anemia is called ____ and is located on Chromosome ___.
HBB; 11
HBB helps in the creation of ____ in the body by coding for the ____ or _____.
hemoglobin;
beta chain or beta globulin
Sickle cell anemia results when there is a single point mutation in the HBB gene that changes a ___ become ____which results in a change from the amino acid ____ to ____.
Adenine become thymine;
glutamate to valine
The mutated HBB has valine which then added to the AA chain, it sticks to the hydrophobic area in the ____ of other hemoglobin causing the molecules of hemoglobin to clump together and fibers that form cause the ____ shape.
beta chains; sickle
Sickle cell anemia is generally found in people of ____ descent
African;
In fact 1 in 12 African Americans carry the sickle cell trait. The genetic disorder is also found in people who families come from South or Central America, the Caribbean islands, Mediterranean countries, India, and Saudi Arabia
People with sickle cell anemia cannot contract ____ which means that Africans with the sickle cell trait were able ____ than those who contracted malaria.
Malaria; to live slightly longer
***This process plays a part in the disease’s prevalence in many people of African descent
In ____ thalassemia, there is no detectable normal, B-globin polypeptide synthesized
B0
A thalassemic B-globin gene contains a ______ trasnversion at position ____which results in an abnormal alternative 3’ acceptor splice site
T to G; 116
In the study, the author states that a T116G transversion of IVS1 cause a B0-thallasemia because it leads to an abnormal ____ site.
alternative 3’ acceptor splice
In the study, the author states that a ____ transition of IVS1 causes ___ thallasemia because it leads to an abnormal alternative 3’ acceptor splice site
G110A; B+
In the G110A transition, which causes B+ thalassemia, there is a similar decrease in the amount of mRNA produced as in T116G, however ___ of the mRNA is normally spliced
20%
The T116G transversion mutation results in the creation of a ____ restriction site, as do a number of other thalassemia mutations, and this study demonstrates some of the difficulties in the differential diagnosis of thesis mutation
MaeI
___ thalassemia is when normal beta chains of hemoglobin are produced by in reduced amounts
B+
The demonstration that the IVS1 position 116 mutation creates an MaeI site raises the questions as to whether this mutation can be distinguished from ____ which also creates MaeI sites.
This is important for effective and accurate ____ diagnosis; which is in need, shown by the potential pitfall in diagnosing the thalassemia mutation at IVS1 position 6
other thalassemia mutations; prenatal
____ are premature erythrocytes that require 2 alpha and 2 beta chains for hemoglobin to mature
Reticulocytes
In the T116G transversion, which causes B0- thalassemia, there is ____ fold decrease in the amount of RNA produced with ___ of it being abnormal spliced despite preservation of the normal acceptor splice site at position 130
4; 99%
the 3’ splice site is characterized by an AG, therefore the T116G trasversion in IVS1 results in an abnormal ____ while the normal splice site still remain at 130
This mutation results in B0-thalassemia
alternative acceptor splice site
The 3’ acceptor splice site is characterized by an AG, therefore the G110A transition in IVS1 results in a novel ____ while the normal splice site still remains at 130
This mutation results in B+ Thalassemia
alternative acceptor splice site
No normal detectable B global mRNA = ?
B0- thalassemia
This analysis reveals a dramatic difference in the efficiency with which the abnormal receptor sites are utilized even though the mutations are only ____ away from each other
T116G and G110A
5bp
In eukaryotes _____ refers to the notion that one gene can encode multiple proteins
Alternative splicing
Exons are present in DNA, ____, and ___ while introns are only present in DNA and ____
pre-mRNA, and mRNA;
pre-mRNA
Defective ____ leads to disease
RNA splicing
the primary RNA transcript must be further processed by removing ____
introns
____ has been used to identify disease specific mutations but is only successful some of the time
Exon sequencing
pre-mRNA processing:
Splicing must be accurate to within a ___ base pair since a mistake would throw the whole ___ sequence out of order and scramble the ____ sequences
single; codon; protein
A specific splicing variant associated with cancer is the three human ____ genes.
These genes encode enzymes that ___ a form of epigenetic regulation
DNA methyl transferase (DNMT); add methyl groups to DNA
pre-mRNA processing:
There are several classes of introns. The most frequent class of introns in eukaryotic nuclear genes is the ____ group of introns
GT- AG (or GU-AG in RNA code)
Abnormally spliced DNMT3 and mRMAs are found in ___ and ___cell lines
Expression of two of these abnormally spliced mRNAs in cells causes changes in the DNA methylation patterns in those cells; and cells with one of the abnormal mRNAs also grew twice as fast as control cells (a direct contribution to tumor development)
tumors; cancer
Another specific splicing variant associated with cancer is the ____ protocol-oncogene
Ron (MST1R)
The abnormally spliced transcript of Ron increases levels of SF2/ASF, especially in _____
breast cancer cells
The isoform of the Ron protein encoded by this abnormally spliced mRNA leads to ____ and important property of cancerous cells that helps them move and invade normal tissue
increased cell motility
Beta-thalassemia is caused by point mutations in ______, which may lead to no production of functional beta-globing mRNA or protein
5’ splice site, 3’ splice site, or branch point A
Alternative splicing of Fibronectin mRNA example:
This 75kb gene contain multiple exons; splicing of fibronectin varies by ___ type
The two types in this example are ____ and ____
cell;
fibroblasts and hepatocytes
Causes of Thalassemia include:
- Point mutations in coding regions that alter amino acid sequence of beta-globin
- Mutations in the promoter region of beta-globing gene that cause the gene to not be transcribed and thus not produce beta-globin
_____ is a laminopathy in which there is defective LMNA splicing
Hutchinson-Gilford progeria syndrome
Betha-thalassemia is caused by ____mutation
point
In fibroblasts the ___ and ___ exons encode binding domain for specific protein on the ___
EIIIB and EIIIA; surface
In Hepatocytes these exons are spliced out of mRNA to form
soluble fibronectin
Fibrotic diseases are associated with
Elevated intraocular pressure (IOP)
Increased ___ expression, including ____, in the TM leads to increased _____ leading to elevated IOP = glaucoma
fibronectin; EDA Fibronectin; fibrosis
Formation of the glucocorticoid receptor subunits utilizes _____
alternative slipicing
GRalpha
ligand activated transcription factor
GRbeta:
dominant negative regulator of glucocorticoid activities
Introns are removed from pre-mRNA by splicing carried out by ____
splicesome complex
____expression of ____ (from abnormal splicing) can cause resistance to GC therapy which includes treatments for asthma, IBD, rheumatoid arthritis, and COPD
Increased; GRbeta
Splicesome complex consists of?
several proteins and RNAs in which some specialized small RNA molecules are found only in the nucleus
GCs damage the ____, causing an increase in ____
trabecular meshwork (TM); IOP
A side effect of GC therapy is development of ___ and iatrogenic ____
GC-induced ocular hypertension (GC-OHT); glaucoma
The splicesome consists of several ____, also known as ____
ribonucleoproteins (U1 to U6); “SNURPS”
Glaucoma trabecular meshwork (TM) cells express less ___ compared to normal trebacular meshwork
GRbeta
Since glaucoma express less GRbeta. this makes glaucoma TM cells ____ compared to normal TM cells
more sensitive to Gas
SNURPS assemble at the ___ sites at the ____ boundaries and consists of _____ and _____
splice; intron/exon
snRNA and protein partners
The altered expression of ___ regulate levels of GR alternative splicing
splicesome proteins
Decreased expression of ____ in glaucoma TM cells ___ GRalpha splicing; GRbeta is ___, and ultimately, glaucoma TM cells become more sensitive to GCs
SRp40; favors
lower
___ snRNA recognizes the 5’ splice site at exon 1-intron boundary
U1
____ snRNA recognizes the sequence flanking branch point A
U2
the ____ part of the SNURP supervises the joining reactions in which recognition is due to ____ between RNA and the primary transcript
protein; base pairing
U2 snRNA recognizes the sequence flanking ____
branch point A
The vase majority of introns initiate with ____ and terminate with ____
GU; AG
In the middle of the intron is a special ___ residue used as a branch site during splicing
adenine
pre-mRNA are recognized by ____ of SNURPs
snRNAs
Stages of Spliceosme Assembly:
- U1 binds the 5’ splice site
- U2AF binds the 3’ splice site
- U2 binds the branch site
- U4 and U6 bind to U2
- U6 binds to the downstream exon
A loop forms between by association of ___ and ___
U1 and U2
___ displaces ___ from the splicesome and ___deaprts as well
U6; U1; U4
____ has been used for direct visualization of eukaryotic introns through the R-loop analysis
Electron microscopy
___ Experiment visualizes Introns
R-Loop Analysis
