Generics Midterm Topics (textbook) Flashcards
unstable and dynamic nature of the mutations, which are due to
expansion, within the transcribed region of the affected gene of repeated sequences
expansion of trinucleotides in noncoding regions of RNAs example
CGG in fragile X
affected gene is passed from generation to generation, what occurs
number of repeats may expand to a degree that is pathogenic,
interfering with normal gene expression and function
intergenerational expansion of the repeats accounts for the phenomenon
Anticipation
Anticipation is
appearance of the disease at an earlier age as it is transmitted through a family.
biochemical mechanism most commonly proposed to underlie the expansion of unstable repeat sequences is
slipped mispairing
repeat expansions appear to occur both in
proliferating -sperm
Somatic-neuron
expansion can occur during both
DNA replication
genome maintenance
Class 1: diseases
expansion of noncoding repeats that cause a loss of protein expression
Class 2: disorders
expansions of non- coding repeats that confer novel properties on the RNA
Class 3: diseases
repeat expansion of a codon such as CAG (for glutamine) that confers novel prop- erties on the affected protein
Give example of a Disease that due to the Expansion of Noncoding Repeats That Cause a Loss of Protein Expression
Fragile X syndrome
How is fragile x passed on
X linked
What codon is expanded in fragile x
CGG
On what gene is the expansion of the CGG repeat in the 5′ untranslated region (UTR) in fragile x
FMR1
excessive methylation of cytosines in the promoter, an epigenetic modification of the DNA that silences transcription of the gene is seen in which case
Fragile x
What causes intellectual disability and learning deficits and the non-neurological features of the clinical phenotype in fragile x
loss of the fragile X mental retardation protein (FMRP)
non-neurological features of the clinical phenotype of fragile x are
macroorchidism
connective tissue dysplasia
What is an RNA-binding protein that associates with polyribo- somes to suppress the translation of proteins from its RNA targets
Fmrp
FMRP appears to regulate
translation of proteins required for the formation of synapses
What’s different about Fragile X Tremor/Ataxia Syndrome.
males with full mutations and virtually complete loss of function of the FMR1 gene never develop FXTAS
FXTAS results from
twofold to fivefold increased levels of the FMR1 mRNA present in these patients
pathogenic RNA in FXTAS leads to
formation of intra- nuclear neuronal inclusions, the cellular signature of the disease
Example of Disorders Resulting from Expansions of Noncoding Repeats That Confer Novel Properties on the RNA
Myotonic dystrophy
How is myotonic dystrophy inherited
autosomal dominant
What is myotonic dystrophy characterised by
muscle weakness and wasting,
cardiac conduction defects,
testicular atrophy,
insulin resistance,
cataracts;
there is also a congenital form with intellectual disability
What codon is expanded in myotonic dystrophy
CTG
What gene does CTG expansion in the 3′ UTR for myotonic dystrophy take place
DMPK gene
DMPK gene encodes a
Protein kinase
What is different about myotonic dystrophy 2
No associated congenital presentation
CTG trinucleotide expansion is thought to
underlie an RNA-mediated pathogenesis
MD pathogesesis appears to result from
binding of the CUG repeats to RNA-binding proteins
MD
Many of the RNA-binding proteins seques- tered by the excessive number of CUG repeats are regulators of
Splicing
pre-mRNAs have been shown to have splicing alterations in patients with DM1 such as
cardiac troponin T
How is huntingtons inherited
autosomal dominant
Huntington Disease is a neurodegenerative disorder associated with
chorea, (involuntary, irregular or unpredictable muscle movements)
athetosis loss of cognition,
psychiatric abnormalities
What causes huntingtons
Expansion of codon CAG
In huntingtons, on what gene does expansion to more than 40 repeats of the codon CAG occur
CAG
Huntingtons
repeats of the codon CAG in the HD gene results in
long polyglutamine tracts in the mutant protein,
huntingtin
striking cellular hallmark of Huntingtons
insoluble aggregates of the mutant protein
clustered in nuclear inclusions in neurons
cellular processes disrupted by mutant huntingtin
transcription,
vesicular transport,
mitochondrial fission,
synaptic transmission and plasticity.
mitochondrial abnormalities play important roles in
Huntingtons
increased risk of Alzheimer’s in relatives of affected individuals due to
genetic contribution involving one or more incompletely penetrant genes that act independently, from multiple interacting genes,
Or from some combination of genetic and environmental factors
monogenic Alzheimer’s highly penetrant form of AD that is inherited in
Autosomal dominant
Alzheimer’s
Mutations in three genes encoding which protein
β-amyloid precursor protein
What lead to autosomal dominant AD
β-amyloid precursor protein
presenilin 1,
presenilin 2
What is apolipoprotein E (apo E)
protein component of several plasma lipo- proteins
ε4 allele of APOE modestly increases susceptibility to
nonfamilial AD and influences the age at onset of at least some of the monogenic forms
important pathological abnormalities of AD are
deposition of
-β-amyloid peptide (Aβ)
-tau protein
The Aβ peptide is generated from
βAPP protein
β-amyloid peptide is found in
extracellular amyloid/ senile plaques in the extracellular space of AD brains
Amyloid plaques contain
Aβ peptide
apoE
one of the causes of the neuronal degen- eration in AD
tau neurofibrillary tangles
What is tau
microtubule-associated protein expressed abundantly in neurons
Hyperphosphorylated forms of tau compose the neurofibrillary tangles where
within AD neurons
mutations in the tau gene are associated with
Dementia
βAPP is a single- pass intracellular transmembrane protein found in
endosomes,
lysosomes,
ER
Golgi apparatus
βAPP subject to three distinct proteolytic fates, depending on the relative activity of three different proteases
α-secretase and β-secretase (cell surface)
γ-secretase-cleaves membrane proteins within their transmem- brane domains
monogenic AD due to
missense substitutions in the gene encoding βAPP
Aβ42 peptide is thought to be neurotoxic because
more prone to aggregation than Aβ40
What gene encodes βAPP
APP
mutations in the AD genes presenilin 1 and presenilin 2 lead to
increased production of Aβ42
allele is significantly overrepresented in patients with AD and is associated with an early onset of AD
ε4
Several moder- ately rare missense coding variants in this gene are asso- ciated with a fivefold increase in risk for late-onset AD
TREM2
Mutations in mtDNA can be inherited
maternally
or acquired as somatic mutations
Replicative segregation refers to
multiple copies of mtDNA in each mitochondrion replicate and sort randomly among newly synthesized mitochondria,
are then distributed randomly between the daughter cells
Homoplasmy is
cell contains a pure population of normal mtDNA or of mutant mtDNA
(Vice versa for hetro)
mitochondrial disorders are generally char- acterized by
reduced penetrance,
variable expression,
pleiotropy
maternal inheritance of mtDNA reflects
mtDNA is almost always inherited entirely from the mother
three types of mutations have been identified in mtDNA
rearrangements cause deletions or duplications of the mtDNA molecule;
point mutations in tRNA or rRNA genes impair mitochondrial protein synthesis;
missense mutations in the coding regions of genes, alter activity of an oxidative phosphorylation protein
Kearns- Sayre syndrome caused by
mtDNA deletions
