Lecture 3: Mendelian Disease Part One Flashcards
What are amyloid plaques?
abnormal deposits of protein called beta amyloid that is found in the space between neurons
What are neurofibrillary tangles?
formed by clumps of tau protein which is part of the structure of the microtubules that support the structure of the neuron
What are the consequences of amyloid plaques and neurofibrillary tangles forming?
the synaptic connections between neurons are lost and many neurons stop function and die… atrophy of the brain occurs… this is common in Alzheimer’s Disease
What inheritance pattern do most cases of early onset AD have?
autosomal dominant pattern
What chromosomes are involved in the genetics of AD? Alzheimer’s Disease
1, 14, and 21
What is amyloid precursor protein (APP gene)?
chromosome 21; over 30 mutations of this gene have been associated with early on-set AD
How is chromosome 14 involved in Alzheimer’s disease?
chromosome 14 is presenilin 1 (PSN1); over 150 mutations of this gene have been identified; abnormalitites in this gene lead to overproduction of a longer and more toxic beta amyloid peptide and plaque formation
What is the rarest of the three chromosomes associated with EOAD?
chromosome 1 or presenilin 2 (PSN2)
When does late- onset Alzheimer’s typically occur?
after age 65
What is the most firmly identified gene involved in late-onset Alzheimer’s?
apolipoprotein E (APOE)
On what chromosome is APOE found?
chromosome 19
What are the three alleles of APOE and what is their role in late-onset Alzheimer’s?
APOE epsilon 2- least common allele and appears to reduce risk
APOE epsilon 3- most common allele and has a neutral role in the disease
APOE epsilon 4- found in 10-15% of the population and appears to increase risk for AD and is associated with an earlier onset
When is an individual at the highest risk for late-onset AD?
when a person has two copies of APOE epsilon 4
What are epigenetics?
factors such as diet, chemical exposures and chronic illnesses can alter the DNA of genes causing certain genes to be switched on or off
What is one process that can alter which genes are transcribed and which are not?
DNA methylation
When can genetic testing in AD occur?
early-onset AD families may choose to be tested for the 3 genes that increase risk for early onset AD
What type of inheritance is Huntington’s Disease?
autosomal dominant inheritance
What % chance does a child of an individual with HD have of getting the disease?
50% chance
What are the manifestations associated with Huntington’s disease?
chorea (rapid involuntary movements), gait abnormalities, abnormal slow eye movements, psychiatric abnormalities, loss of insight, memory loss, weight loss
On which chromosome do HD genes exist?
chromosome 4
What does the mutated form of HD gene consist of?
an expanded CAG trinucleotide repeat
What is CAG the codon for?
glutamine
What causes earlier onset and higher severity of HD?
the higher the number of CAG repeats
What is the significance of inheriting the HD allele from the father?
there is a three year earlier onset of the disease
What is a positive test result in HD?
more than 40 CAG repeats; always develops HD
What is a negative test result in HD?
less than 35 CAG repeats
What is the most common lethal inherited disorder among Caucasians in the U.S.?
cystic fibrosis
How is cystic fibrosis inherited?
in an autosomal recessive patter; both copies of gene must be present for disease
Cystic fibrosis is caused by a defect on which gene?
chromosome 7; cystic fibrosis transmembrane conductor regulator (CTFR)
What is the purpose of the CTFR gene?
helps regulate chloride channels in epithelial cells; channels allow for chloride to be excreted and excess sodium uptake is inhibited; water content of secretions is maintained
What happens a patient with CF in regards to the chloride transport system?
defective chloride transport across the membrane and enhanced sodium absorption causes increase in water absorption
What are the manifestations of cystic fibrosis?
failure to thrive/ impaired growth, chronic pulmonary infections, nasal polyps, chronic cough, abnormal lung parenchyma, right sided heart failure, pancreatic inflammation, steatorrhea (increased fat in stool), biliary cirrhosis, liver damage, portal hypertension
What is significant about CF in males?
98% are infertile due to absence of vas deferens
Which form of neurofibromatosis is more common?
NF1 is more common than NF2
What is a neurofibroma?
a benign encapsulated tumor composed of Schwann cells tat are ectodermal in origin
How many cases of NF1 are inherited and how many result from new mutations?
50% inherited
50% new mutations
What is the inheritance pattern of NF1?
autosomal dominant disorder
What is NF1 gene main function?
tumor suppressor gene
Does NF1 gene have complete penetrance?
Yes.
What are café-au-lait macules?
they appear during the first year of birth and 6 or more is highly suggestive of NF1
What are Lisch nodules?
small hamartomas of the iris; more common in adult NF1 patients
What are a few manifestations of NF1?
cutaneous neurofibroma, plexiform neurofibroma, optic glioma; bony abnormalities like bowing of legs, scoliosis, short stature, and osteoporosis
What is NF2?
cause development of noncancerous tumors on the auditory and vestibular nerves of the body; tumors are known as schwannomas and are usually bilateral; tumors can occur in CNS; symptoms typically present later in life
On what gene is the chromosome for NF2 found?
chromosome 22
What does NF2 gene encode for?
protein called merlin (tumor suppressor gene)
What is the inheritance pattern for NF2?
autosomal dominant inheritance
How does polycystic kidney disease typically manifest?
as bilateral renal cysts but it can be a multi-organ disease
How is polycystic kidney disease typically transmitted?
in an autosomal dominant pattern; rarely follows an autosomal recessive pattern
What are the mutations for polycystic kidney disease?
PKD1 or PKD2
On which chromosome is PKD1 located and what does it encode for?
chromosome 16 and encodes for polycystin-1
What is the difference between PKD1 and PKD2?
PKD1 is 85% of the disease and has increased severity of symptoms; PKD1 also has younger onset of symptoms
On which chromosome is PKD2 located and what does it encode?
on chromosome 4 and it encodes polycystin-2