Final Exam Review Flashcards
What are the two functional roles of genes?
- Housekeeping: maintenance of cell structure and function; in all cells (ex: actin, tubulin)
- Specialty: tissue specific proteins with unique functions (ex: liver enzymes)
Describe the impacts of mutations of housekeeping genes and specialty genes
Mutation in housekeeping genes: ebryonic lethal or genetic redundancy if there is genetic redundancy
Mutation in specialty gene: tissue/ organ specific effect
Both can have broader effects if the defect impacts a diffusible factor or global physiology
What is allelic heterogeneity?
In different families, distinct/unique allelomorphs impacting the same gene cause distinct phenotypes between families
Due to presence of multiple alleles at a single locus
What is the difference between allelic heterogeneity and penetrance/expressivity?
Allelic heterogeneity describes differences in different families with mutations in same gene, but different alleles
Penetrance/expressivity describes differences within a family that has mutations in a single allele, but show different phenotypes
What is locus heterogeneity?
Different, unique gene mutations have impact on the same trait. This is because multiple locii may be associated with a specific clinical condition
Why does locus heterogeneity complicate clinical interventions?
Drugs usually target specific proteins or receptors, but locus heterogeneity results in different proteins/receptors that are affected, so different drugs would be needed
What is clinical heterogeneity?
Distinct phenotypic characteristics are seen in different patients with the same or very similar genotypes
What is pleiotropy?
When a mutation affects different biochemical pathways, or anatomical, biochemical or behavioral characteristics, distinct effects in different regions of the body are often seen
Compare the impact of typical hypomorphic mutations and amorphic mutations
Hypomorphs often have less severe impacts on health than amorphs
Some function is better than none
In enzymopathies, are genotype and phenotype usually correlated?
Yes. Catalysis happens in real time, so affected enzymes are unable to properly produce the proteins that are responsible for the phenotype
Describe the most common mutations found in aminoacidopathies.
Most involve loss of function alleles in genes coding for degrading enzymes or mutations of genes that impact cofactors
What is the name of the enzyme responsible for phenylalanine degration?
Phenylalanine hydroxylase (PAH)
converts phenylalanine to tyrosine
requires a co-factor tetrahydrobiopterin (BH4)
In what organs can you find PAH?
The liver and the kidney
Describe Phenylketonuria (PKU)
Phenyl-keton-uria = phenyl ketones detected in urine
Disease of amino acid metabolism where Phe accumulates in all body fluids because it can’t be converted to Tyr due to the absence/deficiency in PAH
What is the genotype of most PKU patients?
They are usually compound heterozygotes with combinations of hypo/amorphic alleles that impact the disease course and treatment
What is hyperphenylalaninemia?
Dramatic increase in blood [Phe] seen in PKU patients
What is the clinical impact of hyperphenylalaninemia?
Almost all untreated PKU have severe mental retardation due to neurotoxicity
Need to diagnose within 4 weeks of birth to prevent negative outcomes (>24 hours after birth because of peak in [Phe] at birth)
What is the main treatment for Classic PKU?
Maintaining a low phenylalanine diet
What is the blood phenylalanine level typically seen in PKU? What is the normal range?
Classic PKU: >20 mg/dL Phe
Wildtype” ~0.5-1 mg/dL Phe
What type of alleles are associated with Variant and Non-PKU/Benign HyperPhe?
Hypomorphic alleles
The impact is less severe than classical PKU
What are the typical phenotypes observed in PKU heterozygotes?
They show minor or no phenotypes
Describe the steps taken for treating pregnant mothers with PKU
They must treat the PKU by watching their diet in order to prevent the fetus from being flooded with Phe, which leads to mental retardation, heart defects…etc.
Describe the locus heterogeneity of BH4 metabolism
BH4 acts as a hydrolase cofactor in biosynthetic pathways including:
Phe –> Tyr
Tyr –> L-dopa
trp –> 5-OH trp –> serotonin
What are the supplements and medication needed to treat compound heterozygotes or homozygotes with reduced BH4?
Oral BH4
Low Phe diet
L-dopa
5 OH-Trp
Folinic Acid
Why is it important to distinguish patients with PAH mutations from BH4 metabolism defects?
Treatment of these patients differs
What are lysosomes?
Membrane bound organelles containing many hydrolytic enzymes where many proteins and lipids are degraded
What is the typical effect of lysosomal storage diseases?
Overaccumulation of substrates leads to cell death
Organ mass changes and/or neurodegeneration are common
What are the relevant molecules involved in spingolipid degradation diseases?
The GM2 Gangliosides accumulate because hexosaminidase A function is lost
Describe hexosaminidase A
It is a multisubunit enzyme that requires a recognation subunit (activator) to present GM2 to the HEXA and HEXB Enzyme Core
It cleaves off the monosaccharide N-acetylgalactosamine (GalNAC)
Without this cleavage, GM2 accumulates in the lysosome
Describe the mutation seen in Tay-Sachs disease
Compound heterozygotes for loss of function alleles of the HexA alpha subunit gene
What are three population genetics theories that could explain why Tay-Sachs disease is common in some populations? Which is the predominent theory?
- Heterozygote advantage
- Founder effects in a small population
- Genetic drift
Describe the phenotype seen in Tay-Sachs disease
Normal behavior and growth until about 3-6 months of age
Seizures common at early age, the rapid neurological degeneration occurs with a loss of motor control
Can see neuronal death in the eye’s Fovea Centralis
Describe the allelomorphy seen in Tay-Sachs disease
A complete loss of function (amorphic) allele prevents Hex A from having any activity
This is a 4 nucleotide insertion that alters the reading frame leading to a premature stop codon
Describe HexA Pseudodeficiency
have about 20% residual hexA activity, which is enough to prevent the neurodegeneration. Homozygotes display normal phenotypes.
What aminio acid is associated with homocystinuria?
Methionine
What happens in homocystinuria?
There is a build up of homocysteine in the cells which causes:
Lens dislocation, mental retardation, osteoporosis, and increased bone length
Thromboembolism of veins and arteries
What happens in patients with α-Antitrypsin Deficiency?
In liver there is a neomorphic mutation (Glu342Lys) which leads to aggregation into long polymer strands in the hepatocyte Rough ER
The α1AT is a serine protease inhibitor (serpin) that binds and inhibits elastase
The improper balance of α1AT/Elastase leads to lung disease
What behavior significantly lowers the 60 year survival rate on α-Antitrypsin deficient patients?
Smoking
What is the main characteristic seen in hyperlipoproteinemias?
High levels of blood plasma lipids and lipoproteins
Describe the mutation usually seen in hyperlipoproteinemias
Dominant traits from loss of function alleles
Most common: LDL receptor loses function due to autosomal dominant inheritance pattern. This causes LDL cholesterol level to rise to ~350 mg/dL in heterozygotes (700 in homozygotes)
What is pathway interaction theory?
A thoery that explains the interactions between enzymes and substrates in a linear fashion
Linear dependent: A–>B–>C “A is required for B, is required for C”
Linear negative: A–||B–||C “A inhibits B, which inhibits C”
Partner effect pathways: A<—>B “A is required for B is required for A …”
Describe hypercholesterolemia using pathway interaction theory
Hypercholesterolemia is a complex partner effect pathway inhibited by a linear negative feedback pathway.
What are the proteins associated with hypercholesterolemia?
- Mature LDL receptors on cell membrane
- Apoprotein B-100 protein surrounding cholesterol ester core, binds to LDL receptor
- PCSK9: protease that degrades LDL receptor
- ARH adaptor protein: required for clustering the LDL receptor in the clathrin coated pit
What is the gene dosage effect, and how is it related to hypercholesterolemia?
Homozygotes with this disease have twice the serum cholesterol level of heterozygotes, symptoms manifest earlier and are more severe
What are the classes of mutations in the LDL receptor?
1) Receptor synthesis
2) Receptor transport from ER to Golgi
3) LDL binding by receptor
4) Receptor clustering in coated pit
5) Failure to discharge LDL in endosome
6) Defective targeting to basolateral membrane
What are the structural domains of the LDL receptor?
1) Ligand binding domain
2) EGF precursor homology domain
3) Transmembrane domain
4) Cytoplasmic tail
Describe the general genetic effect of Cystic Fibrosis
An autosomal recessive allele that is usually loss of function
Chloride Ion Transporters (CFTR) mutations cause abnormal fluid balance across the membrane
Problem in epithelial tissues that secrete fluid (i.e. Lungs, pancreas …)
What are the 3 domains of the CFTR protein?
Membrane Spanning domain
Nucleotide binding domain
Regulatory domain
What are the classes of mutations in CFTR gene and cellular effects?
1) no synthesis of gene product
2) Defective protein product destroyed in proteosomes
3) Protein gets to cell surface, abnormally regulated
4) Defective chloride ion conductance
5) Promotor, intron/exon splicing mutatnts
6) Increased rate of turnover of Cl channels at the cell surface
Is the presence of the CFTR genotype a good predictor of pulmonary disease?
No. Amorphs and Hypomorphs have variable impacts on lung function. Different alleles moderate/enhance the CFTR mutation
What are the major examples of a structural protein mutation?
Dystrophin mutations that cause Ducenne and Becker Muscular Dystrophy.
Collagen mutations can cause Osteogenesis Imperfecta
Describe Duchenne Muscular Dystrophy
An X-linked disorder, which meens most affecteds are males
A deletion or point mutation leads to no Dystrophin production (Amorph)
Progression: 3-5 y.o. develop muscle weakness, confined to a wheelchair by 12 y.o. and dead by 20 y.o.
Respiratory and cardiac failure usually cause death. Elevated levels of serum creatine kinase are seen
What is the difference between Becker Muscular Dystrophy and Duchenne Muscular Dystrophy?
BMD has a much milder phenotype than DMD because BMD affecteds still produce some dystrophin (Hypomorph)
Describe the histological changes seen in the muscles of patients with DMD
Normal muscle tissue has tight muscle fiber bundles pressed together evenly, but DMD affecteds have accumulation of fat and connective tissue between the muscle cells.
What is the prognosis for patients with BMD?
Ambulatory until 16-30 y.o.
Extensive survival into adulthood
Reproductively fit males
What genes are affected by Osteogenesis Imperfecta?
The collagen genes: COL1A1 or COL1A2
Describe the phenotype of individuals with Osteogenesis Imperfecta
Characterized by brittle bones due to malformed collagen fibers.
Phenotypes are highly variable due to many allelomorphs
Describe the normal collagen structure
Collagen is a heterotrimer containing 2 procollagen-1A1 and 1 procollagen-1A2 molecules that form into a triple helix
What are the differences between Type I and Type II, III and IV Osteogenesis Imperfecta
Type I: Diminished Type 1 Collagen production usually due to a premature stop codon in COL1A1
Type II, III, IV: Structurally defective collagen usually due to the replacement of a Glycine residue with a more bulky amino acid residue