Generics Midterm Topics (textbook) Flashcards
(178 cards)
1
Q
unstable and dynamic nature of the mutations, which are due to
A
expansion, within the transcribed region of the affected gene of repeated sequences
2
Q
expansion of trinucleotides in noncoding regions of RNAs example
A
CGG in fragile X
3
Q
affected gene is passed from generation to generation, what occurs
A
number of repeats may expand to a degree that is pathogenic,
interfering with normal gene expression and function
4
Q
intergenerational expansion of the repeats accounts for the phenomenon
A
Anticipation
5
Q
Anticipation is
A
appearance of the disease at an earlier age as it is transmitted through a family.
6
Q
biochemical mechanism most commonly proposed to underlie the expansion of unstable repeat sequences is
A
slipped mispairing
7
Q
repeat expansions appear to occur both in
A
proliferating -sperm
Somatic-neuron
8
Q
expansion can occur during both
A
DNA replication
genome maintenance
9
Q
Class 1: diseases
A
expansion of noncoding repeats that cause a loss of protein expression
10
Q
Class 2: disorders
A
expansions of non- coding repeats that confer novel properties on the RNA
11
Q
Class 3: diseases
A
repeat expansion of a codon such as CAG (for glutamine) that confers novel prop- erties on the affected protein
12
Q
Give example of a Disease that due to the Expansion of Noncoding Repeats That Cause a Loss of Protein Expression
A
Fragile X syndrome
13
Q
How is fragile x passed on
A
X linked
14
Q
What codon is expanded in fragile x
A
CGG
15
Q
On what gene is the expansion of the CGG repeat in the 5′ untranslated region (UTR) in fragile x
A
FMR1
16
Q
excessive methylation of cytosines in the promoter, an epigenetic modification of the DNA that silences transcription of the gene is seen in which case
A
Fragile x
17
Q
What causes intellectual disability and learning deficits and the non-neurological features of the clinical phenotype in fragile x
A
loss of the fragile X mental retardation protein (FMRP)
18
Q
non-neurological features of the clinical phenotype of fragile x are
A
macroorchidism
connective tissue dysplasia
19
Q
What is an RNA-binding protein that associates with polyribo- somes to suppress the translation of proteins from its RNA targets
A
Fmrp
20
Q
FMRP appears to regulate
A
translation of proteins required for the formation of synapses
21
Q
What’s different about Fragile X Tremor/Ataxia Syndrome.
A
males with full mutations and virtually complete loss of function of the FMR1 gene never develop FXTAS
22
Q
FXTAS results from
A
twofold to fivefold increased levels of the FMR1 mRNA present in these patients
23
Q
pathogenic RNA in FXTAS leads to
A
formation of intra- nuclear neuronal inclusions, the cellular signature of the disease
24
Q
Example of Disorders Resulting from Expansions of Noncoding Repeats That Confer Novel Properties on the RNA
A
Myotonic dystrophy
25
How is myotonic dystrophy inherited
autosomal dominant
26
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
27
What codon is expanded in myotonic dystrophy
CTG
28
What gene does CTG expansion in the 3′ UTR for myotonic dystrophy take place
DMPK gene
29
DMPK gene encodes a
Protein kinase
30
What is different about myotonic dystrophy 2
No associated congenital presentation
31
CTG trinucleotide expansion is thought to
underlie an RNA-mediated pathogenesis
32
MD pathogesesis appears to result from
binding of the CUG repeats to RNA-binding proteins
33
MD
Many of the RNA-binding proteins seques- tered by the excessive number of CUG repeats are regulators of
Splicing
34
pre-mRNAs have been shown to have splicing alterations in patients with DM1 such as
cardiac troponin T
35
How is huntingtons inherited
autosomal dominant
36
Huntington Disease is a neurodegenerative disorder associated with
chorea, (involuntary, irregular or unpredictable muscle movements)
athetosis loss of cognition,
psychiatric abnormalities
37
What causes huntingtons
Expansion of codon CAG
38
In huntingtons, on what gene does expansion to more than 40 repeats of the codon CAG occur
CAG
39
Huntingtons
repeats of the codon CAG in the HD gene results in
long polyglutamine tracts in the mutant protein,
huntingtin
40
striking cellular hallmark of Huntingtons
insoluble aggregates of the mutant protein
clustered in nuclear inclusions in neurons
41
cellular processes disrupted by mutant huntingtin
transcription,
vesicular transport,
mitochondrial fission,
synaptic transmission and plasticity.
42
mitochondrial abnormalities play important roles in
Huntingtons
43
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
44
monogenic Alzheimer’s highly penetrant form of AD that is inherited in
Autosomal dominant
45
Alzheimer’s
Mutations in three genes encoding which protein
β-amyloid precursor protein
46
What lead to autosomal dominant AD
β-amyloid precursor protein
presenilin 1,
presenilin 2
47
What is apolipoprotein E (apo E)
protein component of several plasma lipo- proteins
48
ε4 allele of APOE modestly increases susceptibility to
nonfamilial AD and influences the age at onset of at least some of the monogenic forms
49
important pathological abnormalities of AD are
deposition of
-β-amyloid peptide (Aβ)
-tau protein
50
The Aβ peptide is generated from
βAPP protein
51
β-amyloid peptide is found in
extracellular amyloid/ senile plaques in the extracellular space of AD brains
52
Amyloid plaques contain
Aβ peptide
apoE
53
one of the causes of the neuronal degen- eration in AD
tau neurofibrillary tangles
54
What is tau
microtubule-associated protein expressed abundantly in neurons
55
Hyperphosphorylated forms of tau compose the neurofibrillary tangles where
within AD neurons
56
mutations in the tau gene are associated with
Dementia
57
βAPP is a single- pass intracellular transmembrane protein found in
endosomes,
lysosomes,
ER
Golgi apparatus
58
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
59
monogenic AD due to
missense substitutions in the gene encoding βAPP
60
Aβ42 peptide is thought to be neurotoxic because
more prone to aggregation than Aβ40
61
What gene encodes βAPP
APP
62
mutations in the AD genes presenilin 1 and presenilin 2 lead to
increased production of Aβ42
63
allele is significantly overrepresented in patients with AD and is associated with an early onset of AD
ε4
64
Several moder- ately rare missense coding variants in this gene are asso- ciated with a fivefold increase in risk for late-onset AD
TREM2
65
Mutations in mtDNA can be inherited
maternally
or acquired as somatic mutations
66
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
67
Homoplasmy is
cell contains a pure population of normal mtDNA or of mutant mtDNA
(Vice versa for hetro)
68
mitochondrial disorders are generally char- acterized by
reduced penetrance,
variable expression,
pleiotropy
69
maternal inheritance of mtDNA reflects
mtDNA is almost always inherited entirely from the mother
70
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
71
Kearns- Sayre syndrome caused by
mtDNA deletions
72
an example of gonadal mosaicism is Kearns Sayre syndrome because it’s inherited from
unaffected mother, who carries the deletion in her oocytes but generally not elsewhere
73
three types of mutations in mtDNA
rearrangements make 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.
74
somatic mtDNA deletions are common in dopami- nergic neurons of the substantia nigra in normal patients and more so patients with
Parkinson disease
75
The tRNA mutations include 18 substitutions in the tRNAleu(UUR) gene cause a phenotype referred to as MELAS
mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes
76
12S rRNA mutation is a homoplasmic substitution that causes
sensorineural prelingual deafness
after exposure to aminoglycoside antibiotics
77
there is a phenotypic threshold effect associated with
mtDNA heteroplasmy
78
neuromuscular system is the one most commonly affected by mutations in mtDNA; consequences can include
encephalopathy,
myopathy,
ataxia,
retinal degeneration,
loss of function of the external ocular muscles
79
Mitochondrial myopathy is characterized by
ragged-red muscle fibers
80
Muscle fibres are affected in mitochondrial myopathy because
proliferation of structurally and biochemically abnormal mitochondria in muscle fibers
81
mitochondrial genetic bottleneck is
restriction and subsequent amplification of mtDNA during oogenesis
HETEROPLASMY AND MITOCHONDRIAL DISEASE
82
most common mtDNA mutation
3243A>G substitution in the tRNAleu(UUR) gene
MELAS
83
3243A>G substitution in the tRNAleu(UUR) gene just mentioned in the context of the MELAS phenotype leads to
diabetes
deafness
chronic progressive external ophthalmoplegia
84
Leber hereditary optic neuropathy
painless bilateral loss of central vision due to optic nerve atrophy in young adults
85
α1-Antitrypsin deficiency
autosomal recessive
86
α1-Antitrypsin (α1AT) deficiency associated with a substantial risk for
chronic obstructive lung disease (emphysema)
and cirrhosis of the liver
87
α1AT protein belongs to protease inhibitor family
SERPINA1
88
What inhibits elastase released from neutrophils in the lower respiratory tract
α1AT
89
Which relatively common α1AT allele is associated with an increased risk for lung or liver disease
Z allele
Glu342Lys
90
α1AT gene expressed principally in the liver, which normally secretes
α1AT into plasma
91
Some Z/Z homozygotes can present with
Neonatal jaundice
92
Those presenting with jaundice from Z/Z homozygotes can develop
cirrhosis
93
Z allels may arise from mutant protein, this protein
aggregate,
trapping it within the rough endoplasmic reticulum (ER) of hepatocytes
94
Z protein aggregation is a consequence of
structural changes in the protein that predispose to the formation of long beadlike necklaces of mutant α1AT polymers
95
lung disease associated with the Z allele of α1AT deficiency is due to
alteration of the normal balance between elastase and α1AT,
allows progressive degradation of the elastin of alveolar walls
96
Both sickle cell disease and the α1AT deficiency asso- ciated with homozygosity for the Z allele are examples of
inherited conformational diseases
97
molecular explanation for the effect of smoking is that
active site of α1AT, at methionine 358, is oxidized by both cigarette smoke and inflammatory cells,
reducing its affinity for elastase
98
porphyria inherited by
autosomal dominant
99
porphyria associated with intermittent neurological dysfunction primarily defect is
deficiency of porphobilinogen (PBG) deaminase,
enzyme in the biosynthetic pathway of heme,
required for the synthesis of hemoglobin and hepatic cytochrome p450 drug-metabolizing enzymes
100
normal individuals the drug-related increase in ALA synthetase is beneficial because
increases heme synthesis, allowing greater formation of hepatic cytochrome P450 enzymes that metabolize many drugs
101
Familial Hypercholesterolemia leads to a greatly increased risk for myocardial infarction, is characterized by
elevation of plasma cholesterol carried by LDL,
102
Familial hypercholesterolemia is a hyperlipoproteinemia, what are the characteristics
elevated levels of plasma lipids carried by apo- lipoprotein B containing lipoproteins
103
Familial Hypercholesterolemia has mutations in
LDL receptor gene
104
genes associated with familial hypercholesterolemia disrupt
function or abundance either of the LDL receptor at the cell surface or
of apoB, the major protein component of LDL and a ligand for the LDL receptor.
105
mutations in the PCSK9 protease gene gain causes hypercholesterolemia, what else occurs
common loss-of-function sequence variants lower plasma LDL cholesterol levels,
conferring substantial protection from coronary heart disease
106
most common cause of familial hypercholesterolemia
Mutations in the LDL receptor gene
107
Elevated plasma concentrations of LDL cholesterol lead to
premature atherosclerosis (accumulation of cholesterol by macrophages in the subendothelial space of major arteries
108
Physical stigmata of familial hypercholesterolemia include
xanthomas- cholesterol in skin and tendons
premature arcus corneae, cholesterol around cornea
109
Familial hypercholesterolemia due to mutations in the LDLR gene is inherited as an
autosomal semidominant trait
110
Receptor-bound LDL is brought into the cell by endocytosis of the coated pits, which ultimately evolve into lysosomes in which
LDL is hydrolyzed to release free cholesterol
111
The increase in free intracellular cholesterol reduces endogenous cholesterol formation by suppressing the rate-limiting enzyme of the synthetic pathway
3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase
112
Class 1 mutations are null alleles
prevent the
synthesis of any detectable receptor; they are the most common type of disease-causing mutations at this locus
113
class 2 mutations are designated transport-deficient because
LDL receptors accumulate at the site of their synthesis, the ER, instead of being transported to the Golgi complex.
114
Class 3 mutant receptors reach the cell surface but
are incapable of binding LDL.
115
Class 4 mutations impair localization of the receptor to the coated pit, and consequently
bound LDL is not internalized.
mutations alter or remove the cytoplasmic domain at the carboxyl terminus of the receptor,
116
Class 5 recycling-defective alleles
Mutations in the epidermal growth factor precursor homology domain prevent
release of the LDL ligand. This failure leads to degradation of the receptor,
117
Class 6 mutations lead to defective targeting of the mutant receptor to the basolateral membrane
Mutations affecting the signal can mistarget the mutant receptor to the apical surface of hepatic cells
impairing the recycling of the receptor to the basolateral membrane and leading to an overall reduction of endocytosis of the LDL receptor.
118
Rare cases of autosomal dominant familial hypercholes- terolemia have been found to result from gain-of- function missense mutations in
gene encoding PCSK9 protease
119
role of PCSK9 is to
target the LDL receptor for lysosomal degradation,
reducing receptor abundance at the cell surface
120
More LDL receptors increase
cellular uptake of LDL cholesterol, lowering cholesterol and providing protection against coronary artery disease
121
cystic fibrosis (CF) inheritance
autosomal recessive
122
pancreatic defect in CF is a maldigestion syndrome due to
deficient secretion of pancreatic enzymes (lipase, trypsin, chymotrypsin)
123
neonatal lower intestinal tract obstruction of cf babies is called
meconium ileus
124
females with CF have some reduction in
Fertility
125
95% of CF males are infertile because
lack the vas deferens
126
CF is due to abnormal fluid and electrolyte transport across epithelial apical membranes, This abnormality leads to
disease in the lung, pancreas, intestine, hepatobiliary tree, and male genital tract
127
loss of CFTR function means that chloride in the duct of the sweat gland
cannot be reabsorbed
128
In the lung, the hyperabsorp- tion of sodium and reduced chloride secretion result in a
depletion of airway surface liquid.
129
major cause of chronic pulmonary infection in CF.
Pseudomonas aeruginosa
130
most common CF mutation is
deletion of a phenylalanine residue at position 508 (ΔF508) in the first ATP-binding fold (NBD1
131
Mutations in cf
Half missense
Rest are point
132
Other that CFTR, what gene can carry mutations in CF
SCNN1
133
1-4 risk foetus Cf prenatal diagnosis by DNA analysis at 10 to 12 weeks,
obtained by chorionic villus biopsy
134
Dmd inheritance
X-linked disorder
135
Dmd boys are normal for the first year or two of life but develop muscle weakness by 3 to 5 years of age what can they have difficulty with
climbing stairs and rising from a sitting position. The child is typically confined to a wheelchair by the age of 12 years.
136
Dmd preclinical and early stages of the disease, the serum level of
creatine kinase is grossly elevated
137
Becker muscular dystrophy (BMD) is also due to mutations in
dystrophin gene
138
BMD alleles produce a
much milder phenotype
139
Dystrophin is detected more in which dystrophy
BMD
rather than DMD
140
most common molecular defects in patients with DMD are
deletions
141
Prenatal Diagnosis and Carrier Detection of md
examination of fetal DNA
142
Osteogenesis imperfecta (OI) is a group of inherited disorders that
predispose to skeletal deformity and easy fracturing of bones,
143
Which genes do mutation occur for OI
COL1A1 and COL1A2
144
COL1A1 and COL1A2, that encode the chains of
type I collagen, the major protein in bone
145
Novel Forms of Osteogenesis Imperfecta
mutations in the IFITM5 gene
WNT1
BMP1
146
mutations that produce structurally abnor- mal proα2(I) chains reduce the number of
the number of normal type I collagen molecules by half,
147
bone marrow transplantation and enzyme replacement therapy have dramatically improved the prognosis of
Lysosomal Storage Diseases
148
Tay-Sachs Disease - genes that cause it
HEXA and HEXB genes
149
Tay sachs
Affected infants appear normal until approximately 3 to 6 months of age but then
gradually undergo progres- sive neurological deterioration until death at 2 to 4 years.
150
Tay sachs
effects of neuronal death can be seen directly in the form of
cherry-red spot in retina
151
Tay sachs
HEXA alleles associated with some residual activity lead to later-onset forms of neurological disease, with manifestations including
neurological disease, with manifestations including lower motor neuron dysfunction and ataxia due to spi- nocerebellar degeneration.
152
Low level hex A activity
prevent GM2 ganglioside accumulation in the brain
153
Tay sachs
correct characterization of individuals
screening or diagnos- tic tests
154
HEMOGLOBINOPATHIES
Structural variants, which alter
amino acid
sequence of the globin polypeptide, altering properties such as its ability to transport oxygen, or reducing its stability
155
Thalassemias are diseases that result from
decreased abundance of one or more of the globin chains
156
Hereditary persistence of fetal hemoglobin, a group of clinically benign conditions that impair
perinatal switch from γ-globin to β-globin synthesis
157
Most variant hemoglobins result from
point mutations in one of the globin structural genes
158
Variants that cause hemolytic anemia
make the hemoglobin tetramer unstable.
159
Variants with altered oxygen transport
increased or decreased oxygen affinity or to the formation of methemoglobin, a form of globin incapable of reversible oxygenation.
160
Variants due to mutations in the coding region that cause thalassemia
reduce the abundance of a globin polypeptide.
161
Sickle cell hemoglobin substitution
codon of the sixth amino acid of β-globin
glutamic acid to valine
162
Sickle cell is caused by
Homozygosity of 6glu val sub
163
Sickle cell inheritance
autosomal recessive
164
Hemoglobin molecules containing the mutant β-globin subunits are normal in their ability to perform their principal function of binding oxygen but
In deoxygenated blood, they are only one fifth as soluble as normal hemoglobin.
165
strong modifier of the clinical severity of sickle cell disease is
patient’s level of Hb F (α2γ2)
166
globin gene and two genes that encode transcription factors,— account for 40% to 50% of the variation in the levels of Hb F in patients with sickle cell disease
BCL11A and MYB
167
Hb F–associated SNPs are also associated with
painful clinical episodes thought to be due to capillary occlusion caused by sickled red cells
168
BCL11A gene is a transcription factor that normally
silences γ-globin expression,
shuts down Hb F production postnatally
169
The unstable hemoglobins are due largely to
point mutations that cause denaturation of the hemoglobin tetramer in mature red blood cells
170
denatured globin tetramers are insoluble and precipitate to form inclusions (Heinz bodies) that contribute to
damage of the red cell membrane and cause the hemolysis of mature red blood cells in the vascular tree
171
Thalassemia damages the membrane and leading to premature red blood cell destruction
chain that is produced at the normal rate is in relative excess (due to mutations) in the absence of a complementary chain with which to form a tetramer, the excess normal chains eventually precipitate in the cell
172
excess β or β-like chains are insoluble and precipitate in both precursors and mature cells causing
erythropoiesis
hemolysis
173
Genetic disorders of α-globin production disrupt the formation of
fetal and adult hemoglobin
174
Hemoglobin with a γ4 composition is known as
Hb Bart’s,
175
β4 tetramer is called
Hb H
176
infants with severe α-thalassemia and high levels of Hb Bart’s (γ4) suffer severe intrauterine hypoxia and are born with
massive generalized fluid accumulation, a condition called hydrops fetalis
177
milder α-thalassemias, an anemia develops because of
gradual precipitation of the Hb H (β4) in the erythrocyte
178
The most common forms of α-thalassemia are
gene deletions
