Nonsense-Mediated RNA Decay Flashcards
Premature termination codons result in what regarding RNA
RNA degradation
premature stop codon results in what
null mutation - no protein
Evolutionarily, why might premature stop codons result in null mutation
to protect against dominant negative effects of truncated proteins
What does EJC stand for
exon junction complex
What do EJCs do
persis on mRNA after splicing and cytoplasmic transport
what displaces EJCs
ribosomes
What is nonsense mediated decay mechanism
it scans the 3’ stalled ribosomes for EJCs
every gene has what regulatory sequence upstream of it
promoter region
what is function of promoter
transcriptional initiation
level of expression
Explain EJCs
pg 135 ppt 2
Where are enhances and silencers located
a distance from gene, can be quite far away
enhancers do what to gene
activate
silencers do what to gene
inhibit gene
silencers are important for level and _____ of expression
specificity
mutations in proximal promoter elemtns usually do what to transcription
prevent
what effect is usually the effect of a mutation in proximal promoter element
null mutation
what is a common birth defect associated with severl syndromes
polydactylyl
What does SHH stand for
sonic hedge hog
what is the function of sonic hedge hog
morphogen - they signal for limb patterning and brain development
mutations in sonic hedge hog cause what
holoprosencephaly
what is holoposencephaly
forebrain fails to develop into 2 hemispheres - usually prenatal lethal
AD polydactylyl had linkage to what
SHH
Where is mutation in AD polydactylyl?
no mutations in SHH gene, enhancer has mutation on intron of LMBR1 gene
In LMBR1 is an ____ for SHH that does what
enhancer that activates expression specifically in the distal limb
Different enhancers can direct expression of the same gene in different _____
tissues
What is lobar holoprosencephaly
only a part of the brain doesn’t develop into two hemispheres normally
where isi the mutation in lobar holoposencephaly
point mutation in enhancer activating SHH expression in specific part of brain during development
What is SBE
SHH brain enhancer
What is ZRS
limb specfific enhancer in LMBR1 described previously
Enhancer mutations far upstream of SHH result in what
polydactyl not holoprosencephaly
Where is mutation in Campomelic Dysplasia
Sox9 (or in 2 enhancers)
skeletal abnormalities, undereveloped shoulders, 11 instead of 12 ribs, is what disease
campomelic dysplaia
Where is Sox9 gene?
Acts downstream of SRY gene (SRY is in charge of making males males)
46 XY who have campomelic dysplasia have what else happen
ambiguous female genitalia
in lactose intolerance what is not expressed
lactase
what disease has inability to metabolize lactose
lactose intolerance
how much of the world is affected by lactose intolerance and why
75% - it is wild type, the normal mammalian phenotype
what does lactose need to be turned into to have body process
galactose & glucose
in regards to lactase what is the mutant phenotype
lactase peristence
what does LP stand for
lactae persistence
In people of european descent what is the most common mutation that leads to lactase persistence?
C to T substitution that leads to increased expression and maintains intestinal expression of lactase
In non-caucasians, where are mutation for lactase persistence?
in different place than for those of european descent
If it’s gain of function what is MOI
AD
For every deletion syndrome there is what
corresponding duplication syndrome
what is the clinical presentation of deletion vs duplication syndrome
some overlap in clinical phenotype
(esp mental retardation and behavioral problems)
will usually see opposite phenotypes
About 1/2 of our genes are expressed where
brain
What is a chromosomal mutation
Gross changes to DNA within chromosomes, multiple genes involved
Eg. Duplications, deletions
Usually due to unequal crossing over during homologous recombination between repeat sequences
What does WBS stand for
Williams-beuren syndrome
Growth abnormalities, very happy, cardiac problems, mentally challenged, is what disease
WBS
Where is chromosomal deletion that causes WBS
7q11.23
What is one of the important deleted genes in WBS?
Elastin (ELN)
What does ELN stand for
Elastin
In WBS the abnormal pairing results in what
deletion & duplication products
In chromosomal diseases for every deletion there should be corresponding
duplication
b/w deletion and duplication which has more severe phenotype
deletions
Autosomal monosomy is always
lethal
Is autosomal trisomy alwyas lethal
no
What is the duplication counterpart to Williams syndrome
WBSCR duplication syndrome
what does WBSCR stand for?
William syndrome critical region
What disease is all neuropathies and has locus heterogenity
charcot-marie tooth disease
what is CMT1A a family of
charcot-marie-tooth disease
Gross changes to DNA within chromosomes, multiple genes involved
Eg. Duplications, deletions
Usually due to unequal crossing over during homologous recombination between repeat sequences
Contiguous Gene Deletion Syndromes Examples: 22q11 Deletion Syndrome (DiGeorge) -thalassemia Williams syndrome
CMT1A
What does HNPP stand for
Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)
Both HNPP and CMT1A map to what chromosome
17p11.2
What gene is affected in HNPP & CMT1A?
PMP22
What is PMP22 function?
major transmembrane protein in myelin
What causes CMT1A and HNPP?
misalignment and recombination b/w flanking repeats
If PMP22 has gain of function what disease
CMT1A
If PMP22 ha loss of function what disease
HNPP
If there are null mutations in PMP22 what disease
HNPP
Missense mutations in PMP22 are what severity vs. CMT1A?
more severe
Missense mutations in PMP22 are what severity vs. CMT1A?
more severe
If Williams syndrome has Long philtrum Full lips Small teeth Normal palate Broad forehead Periorbital fullness and Relative strength in expressive language and Very weak spatial skills what does WBSCR have?
Short philtrum Thin lips Larger teeth Arched palate Narrow forehead Normal periorbital area Severe expressive language delay Relative strength in spatial skills
what is gene conversion
sequence of one gene is replaced by sequence of a similar but not identical allele or gene
it’s similar to recombination but nonreciprocal
What is the result of gene conversion?
it depends on the mismatch repair
What does CAH stand for
congenital adrenal hyperplasia
What gene is involved in CAH
CYP21A2 (21 hydroxylase)
What is CAH?
a group of diseases resulting from deficiencies of enzymes involve din glucocorticoid or mineralcorticoid or sex steroid production
female pseudohermaphroditism
male hypospadias is what disease?
CAH
what is hermaphroditism
sex reversal
what is pseudohermaphroditism
if you are 46 XX you will have external male genitalia but internal female genitalia
what is male hypospadias
urethra is under the penis
In disorders of steroid metabolism what is decreased
aldosterone & cortisol
in disorders of steroid metabolism what is increased
androgens
What is the most common type of CAH
21 hydroxylase deficiency
excessive adrenal androgen biosynthesis
decreased aldosterone and coritosl
salt wasting, hypoglycemia, impaired glucose regulation is what disease
21-Hydroxylase deficiency
Which is the milder form of 21 hydorxylase deficiency?
non-classic form
