mutational mechanism and disease Flashcards
single gene disorders
- loss of function
- gain of function
- novel property mutation
- altered expression mutations
The majority of mutations (currently known) will affect the ______ of the protein
function
Loss of function mutations are the most common example of this
Of the four major mechanisms, this is the most common genetic mechanism leading to human genetic disease.
loss of function
loss of function caused by
by genetic mutations (deletions, insertions, or rearrangements) that eliminate (or reduce) the function of the protein
loss of function examples
- duchenne muscular dystrophy
- a-thalassemia
- turner syndrome
- hereditary neuropathy with liability to pressure palsies
- osteogenesis
Duchenne muscular dystrophy (Case 12):
DMD Xp21.2 Large deletions (multiple exons) Nonsense (stop) mutations / frameshift mutations --> premature termination (in-frame deletions --> milder Becker muscular dystrophy)
Alpha-thalassemia (Case 39)
Alpha-thalassemia (Case 39)
Deletion of alpha globin gene(s)
Turner syndrome (Case 42)
Chromosome deletion
Hereditary neuropathy with liability to pressure palsies
Deletion of gene
(duplication
–> Charcot Marie tooth)
Osteogenesis imperfecta type I
Nonsense (stop) mutations / frameshift mutations
–> premature termination
DMD Xp21.2
Large deletions (multiple exons) Nonsense (stop) mutations / frameshift mutations --> premature termination (in-frame deletions --> milder Becker muscular dystrophy) X-linked inheritance
DMD stands for
duchenne muscular dystophy
DMD clinically:
Boys with abnormal gait at 3-5 years Calf pseudohypertrophy Gower maneuver (YouTube) Progressive involvement of respiratory muscles Median age of death 18 years Women may --> cardiomyopathy
DMD deletions
Frameshift deletions = major loss-of-function mechanism in Duchenne Muscular Dystrophy
In-frame deletions (and also missense mutations) = major loss-of (i.e. reduction)-function in Becker Muscular dystrophy
Hereditary neuropathy with liability to pressure palsies
mutations
Deletion of PMP22 gene = Loss-of-function
–>Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)
PMP22 protein is an integral membrane glycoprotein in nerves
Hereditary neuropathy with liability to pressure palsies
clinically
repeated focal pressure neuropathies (e.g. carpal tunnel syndrome and peroneal palsy with foot drop)
First attack usually in 2nd-3rd decade
Recovery from acute neuropathy is often complete
Incomplete recovery
–> mild disability
Autosomal Dominant
Unequal crossing over between two highly homologous repeats on chromosome 17p12 can result in:
A. 3 copies of the PMP22 gene with the CMT1A phenotype or
B. the reciprocal with 1 copy of the PMP22 gene with the HNPP phenotype.
HNPP and CMT1A are
allelic disorders in the sense that different mutations in the same gene lead to different phenotypes
‘Allelic disorders’ refer to conditions that are
genetically related (due to the same gene most commonly)
Osteogeneis Imperfecta Type I
clinically:
Brittle bones, increased fractures (non-deforming)
blue sclerae
normal stature.
First fracture may occur with diapering, but more typically once infant begins to walk (and fall)
Affected individuals may have anywhere from a few fractures to more than 100M
Progressive hearing loss in adults
OI 1 pathway
Premature termination codons (nonsense and frameshift) in COL1A1
- -> mRNA unstable
- -> mRNA degraded
- -> reduction of normal COL1A1 protein
Autosomal Dominant
OI 1 affects:
The structure of type I procollagen. Note that type I procollagen is composed of two proα1(I) chains and one proα2(I) chain
examples of gain of function
hemoglobin Kempsey
Charcot Marie Tooth Syndrome Type IA
hemoglobin Kempsey gene and mutation
Beta hemoglobin gene
Asp99Asn missense mutation
functions of mutation in beta hemoglobin gene:
- Higher oxygen affinity
- In normal hemoglobin binding of oxygen allowing for shift from tense (deoxygenated) to relaxed (oxygenated) form
99Asn mutation prevents this shift - Hemoglobin remains ‘locked’ in the relaxed state (which has higher
Consequences of hemoglobin kempsey
Hb Kempsey unloads less oxygen in tissues
Body ‘thinks’ it needs more oxygen
–> makes more red blood cells
–> polycythemia
Charcot Marie Tooth Syndrome Type IA
gene mutation
Duplication of PMP22 gene = Gain-of-function
–> Charcot Marie Tooth Syndrome type IA (CMT1A)
PMP22 protein is an
integral membrane glycoprotein in nerves
CMT 1A
clinically
Demyelinating motor and sensory neuropathy
Often presents in lower extremities with weakness and muscle atrophy and mild sensory loss
Progressive; typical patterns on nerve conduction studies
Autosomal Dominant
examples of novel property mutations
sickle cell anemia
sickle cell anemia mutation
No effect on oxygen carrying ability of hemoglobin
Novel property of polymerizing under low oxygen conditions
Long hemoglobin polymers
–> sickle cell shape
In Osteogenesis type I
loss of function mutations –> ½ the amount of total collagen trimers, but it is all normal –>
mild phenotype
In Osteogenesis types II, III, IV
novel property mutations
- -> relatively ‘normal’ amount of total collagen trimers, but ½ is abnormal
- -> severe phenotype
Lesson: better to have_____ normal collagen, than ________ trimers
½ the amount of
produce abnormal collagen
An understanding of the mutation –>
May provide insight into the molecular mechanism (loss of function, gain of function, etc)
–>
May provide clues to the inheritance pattern –>
May set the stage for developing therapies
yep
consequences of mutations
Some key factors: Type of mutation Severity of mutation Target of mutation Protein (target) acts alone versus part of larger network
protein classes where mutations occur
Enzymes receptors Transporters structural nuclear extra-cellular secreted mitochondrial
Tri/tetra nucleotide repeat disorders
- unstable repeat disorders
- largely neurodegenerative
- genetic anticipation
Trinucleotide repeat disorders can affect ______
different parts of a gene (5’, 3’, introns, exons)
fragile X sydrome trinucleotide repeats are located
CGG 5’UTR
txn silencing
loss of function
loss of RNA binding–> impaired translational repression of target RNAs
Fragile X tremor/ataxia syndrom trinucleotide located
5' UTR CGG repeats 2-5 fold increase in FMR1 mRNA gain of mRNA function neuronal intranuclear inclusions
Fredreich ataxia trinucleotide repeats
GAA intron impaired txn elongation loss of function increased Fe in mit reduced heme synthesis redusced Fe-S complex containing protein
Myotonic dystrophy 2
trinucleotide repeats
CCTG
intron
expanded CUG repeat in RNA
increased binding of RNA binding proteins
huntington’’s disease trinucleotide repeats
CAG
exon
expands polyglutamine tracts in huntington protein
loss of function of protein
Myotonic dystrophy 1 trinucleotide repeats
CUG
3’ UTR
expanded CUG repeats in RNA confer to increase amount os RNA binding proteins
correlation btwn CAG and onset huntingtons
Allele sizes (# of CAG repeats)
Normal: < 26
Intermediate: 27-35 (no symptoms; risk of expansion)
Disease +/-: 36-39 (reduced penetrance; risk of expansion)
Disease +: > 40 (~100 % disease; risk of expansion)
Fragile X (_______), Friedreich ataxia (______), and some spinocerebellar ataxias (_______
x linked
autosomal recessive
mostly autosomal dominant, but recessive forms are also reported
Genetic anticipation describes
describes the clinical observation of disease severity worsening in subsequent generations.
Genetic anticipation is explained by
the mechanism of tri/tetra nucleotide repeat number expansions occurring from parent to offspring. The offspring inheriting an expanded disease allele is more likely to present earlier and progress faster.
3 principal pathogenic mechanism
class 1
2
3
class 1 mechanism
Expansion of noncoding repeats and loss of
function
class 1 consequences
Impaired transcription
- Mutant RNA not made -
- Mutant protein not made
class 1 exampels
fragile x
friedreich ataxia
class 2 mechanism
expansion of noncoding repeats conferring novel properties
class 2 consequnces
1. RNA has novel property (abnormal RNA binds and soaks up RNA binding protein --> affects other gene product) 2. mutant RNA is made 3. mmutant protein is not made
class 2 examples
mytotonic dystrophy 1 and 2
fragile X associated tremor/ataxia
(FXTAS)
class 3 mechanism
expansions of codons in exons
class 3 consequences
- novel properties on expressed protein
- mutant RNA is made
- protein is made and IS TOXIC
class 3 examples
- huntingtons
2. spinocerebellar ataxia
Loss-of-Function Mutations:
Mechanisms:
Caused by genetic mutations (deletions, insertions, or rearrangements) that eliminate (or reduce) the function of the protein. Of the four major mechanisms, this is the most common genetic mechanism leading to human genetic disease.
Complete loss of a protein: stop codon, frameshift, or deletion of multiple exons is seen in
Duchenne Muscular dystrophy
Reduction in amount of protein: deletion of copy of
alpha-thalassemia gene
Loss of entire chromosome:
Loss of entire chromosome: Turner syndrome
Somatic mutation leading to loss of tumor suppressor protein:
2nd hit in hereditary
retinoblastoma
Hereditary neuropathy with liability to pressure palsies (HNPP): due to
deletion of
PMP22 gene leading to a phenotype where patients have temporary (usually reversible) neuropathy when pressure is applied to various nerves. Just as your arm may go to sleep if left in a certain position, these patients are more sensitive to pressure on nerves and their limbs can ‘go to sleep’ for longer periods of time (hours, days, to months)
Osteogenesis imperfecta type I: is an example of
Nonsense (stop) mutations / frameshift mutations in COL1A1 –>
premature termination.
Reduced amount of normal COL1A1 (collagen) protein causing a ‘milder’ form of osteogenesis imperfect. Clinically characterized by increased fractures, brittle bones, and blue sclera.
Gain-of-Function Mutations:
Mechanisms:
Caused by genetic mutations (often missense or sometimes promoter mutations) that enhance one or more normal functions of a protein (e.g. increased protein expression, increased half- life, decreased degradation, increased activity)
hemoglobin kempsey gene is
beta hemoglobin gene with asp99Asn mutation
achondroplasia gene and mutation
FGFR3
Gly380ARg
Alzheimers disease gene
APP protein
21q21
charcot marie tooth gene
PMP22
sickle cell anemia gene
Glu6Val
huntington’s disease gene
CAG codon repeat expansion
Ectopic or Heterochronic Expression Mutations: Mechanisms:
Caused by genetic mutations that alter regulatory regions of a gene and alter either the timing (wrong time = heterochronic) or location (wrong place = ectopic) of expression.
examples of novel property mutations include
cancer
hereditary persistence of fetal hemoglobin
unstable repeat sequences
increases from parent to offspring
huntington’s disease
