Recessive Mutations and Human Metabolism Flashcards
What disease lead to the discovery of metabolic genes in humans?
ALKAPTONUREA (metabolic disorder that involves Homogentistic Acid Degradation
This disease led to discovery of metabolic genes in humans
Who was Archibald Garrod and why was he important
Archibald Garrod (1857-1936): doctor who rediscovered Mendelian Genetics, by working with patients. He made insights about how recessive diseases work, and discovered disease called Alkaptonurea
What are the major symptoms of alkaptonuria?
Major symptoms of alkaptonurea;
-Black urine disease, or black bone disease
-Urine blackness on exposure to air
-severe joint pain in older individuals
-sometimes problems with heart, hearing or kidneys
(mostly mild trait, since not a life threatening disease; people still live long)
What is another symptom that occurs with people with Alkaptonurea?
Alkaptonuria alos causes subtle pigment depositions;
-black spots on eyes (become more apparent as you age) , and blackening in the ear
Why is Alpatonuria so ideal for human genetic studies?
Alkaptonuria is ideal because:
-Patients are relatively healthy
-Urine from patients with alkaptonuria reacts strongly with bases, so the trait can be identified EASILY
(ask people from family to provide urine samples, add basic solution and watch if urine darkens, hence you can tell what trait they are, look for patterns of inheritance)
Ex: Experiment left (control) Right (AKU patient)
What percent of children are affected with Alkaptonuria? How was this discovered?
25% of children in a family are usually affected by Alkaptonuria. This was discovered after Archibald observed many urine samples and gathered data in about 18 large families
-he found 19/76 people in LARGE families had Alkaptonuria, which was equivalent to almost 25%I
What kind of mutation is Alkaptonuria? What are the genotypes for parents and children?
RECESSIVE Mutation.
Archibald had punnet square where parents were carriers of the alkaptonuria gene and 25% offspring had recessive mutation
genotypes: Parents were carriers so heterozygous: Aa x Aa
offspring: 1/4 AA, 1/2 Aa, 1/4 aa
aa (alkpatonuria mutation)
Explain why genetic nomenclature is more complicated than Mendel. Differentiate between the convenient genotype and full name used for Alkaptonuria and Achondroplasia
Genetic nomenclature is more complicated for Mendel:
-whenever there are three alleles, and due to limited number of letters in alphabet to represent each genetic disease (two diseases we already know use genotype A a, which can be confusing to distinguish between them, since both diseases start with letter A and use same letter for genotype
-For convenience, we are calling individuals with alkaptonuria genotype aa here
-One full name would be HGD- HGD-
each HGD- is recessive allele
In lecture #2 we called individuals with Achondroplasia genotype Aa
-But one full name would be FGF3^AchG346E FGF3+
FGF3+ is recessive allele
-**we only use genotypes like “aa” when it is convenient and NOT confusing
What kind of disorder is Alkaptonuria and what causes it?
Alkaptonuria is a METABOLIC disorder:
-The disease is caused by a build up of homogentisic acid in the blood and tissues
-Oxidized homogentisic acid is alkapton (black stuff in urine) ,
This chemical is a metabolic intermediate
Explain the biochemical pathway of making homogentisisc acid and how this contributes to development of alkaptonuria. What happens when too much tyrosine is produced?
The amino acid Phenylalanine can be transformed into Tyrosine
-When there is too much tyrosine made, it can be converted to dopamine which will convert to Melanin
OR too much tyrosine can lead to 4-hydroxyphenylpyruvate which will be converted to Homogentisic acid which normally breaks down to other compounds
However, Garrold realized in samples of patients with alkaptonuria, they had a build up of homogentisic acid and concluded that transformation of homogentisic acid into maleylacetoacetate was failing.
The enzyme (homogentisic acid Oxidase) that controlled chemical reaction to converted homogentisisc acid into maleylacetoacetate was DEFECTIVE
hence gene that controlled making enzyme is one associated with alkaptonuria.
Why was Garold’s discovery about alkaptonuria so significant
By looking at biochemical breakdown products and observing urine samples of those with alkaptonuria and observing biochemical pathway, he was able to come up with his own biochemical explanation and theory behind the disease
explanation Those who have alkaptonuira are due to a chemical reaction failing; missing an enzyme that catalyzes the reaction
**product of HGD (homogentisic acid gene) catalyzes breakdown of homogentisic acid
theory: maybe genes control production of enzymes.
alkaptonuia controls enzyme homogentisic acid oxidase.
What are the kind of mutations that cause alkaptonuria?
Mutations that cause Alkaptonuria INACTIVATE the HGD gene
-found missense mutations, splice-site mutations, insertions or deletions (change reading frame) and stop mutations
Why is Alkapontuira a recessive disease? What happens if there is 1 good copy vs 2 bad copies of the HDG gene?
Alkaptonuria is recessive because ONE copy of an enzyme gene is ENOUGH
-2 good copies of gene: HGD gene would make enzyme to catalyze reaction: it make mRNA–>Proteins to turn homogentisic acid and convert to maleoacetylacetate
-if you have one good copy of gene, you will make some of enzyme and some defective piece of protein (can still transform most of the homogentisic acid to maleoacetoacetate
***if you have to BAD copies of gene, and neither copy has ability to make enzyme, you will develop
the disease because they are not making HGD enzyme needed to break down homogentisic acid. This homogentisic acid is just build up in person’s body.
What are the four inborn (genetic) error of metabolism that Garrod identified? What do they all have in common?
Four diseases:
-Alkaptonuria (alkapton in urine)
-Albinism (defects in melanin production)
-Cystinuria (cystine kidney stones)
-Pentosuria (xylulose in urine)
The genetics:
All are autosomal recessive (study siblings)
-Common among children of cousins
Differentiate between the pedigree of a dominate trait vs recessive trait
Dominant trait pedigree: notice that dominant trait is passed down in EVERY GENERATION ; somebody who did not get the dominant trait cannot pass it on to their children or other generations.
Recessive trait pedigree: both parents MUST be carriers of the recessive trait. More common situations where two carriers marry each other and affect children is through having common ancestor; hence Marriage of COUSINS
-CONSAGUINOUS MARRIAGES (marriage of cousins) tend to be common for those affected with recessive traits.
Explain the process of how we can calculate the probabilities of all genotypes in a pedigree
Calculating the probabilities of all genotypes in a pedigree:
1. First, fill in the genotypes of homozygous recessive individuals
2. Next, add unaffected individuals who married into the family
-*** if the allele is rare, they are likely to be HOMOZYGOUS DOMINANT unless proven otherwise by pedigree itself
3. Then fill in obvious genotypes of their children
4. Calculate the probabilities for individuals with inconclusive genotypes
5. Use these probabilities to predict genotypes for successive generations
What is Tay-Sach’s disease and what are symptoms of the disease?
Tay-Sach’s disease: recessive disorder that affects LYZOSOME FUNCTION
Symptoms of Tay-Sachs Disease:
-Between 3-6 months of age, development slows and muscles weaken
-strong startle reaction
-eventually seizures, Vision and hearing loss, and paralysis
-usually fatal in childhood.
(also notice cherry spot on retina in invidividuals with disease )
What happens to the lysosomes in Tay-Sachs patients? How does this work?
Tay-Sachs patients Accumulate Ganglioside GM2 in their lysozomes.
lysosomes normally digest a lot of proteins to help get rid of them and keep cell young and fresh.
you need enzyme Hexoseaminodose A which is in lysosome that will pick up any ganglioside GM2 in the lysosome and digest it, to be dumped out by exocytosis and recycled.
However, people with Tay-Sachs disease contain many digestive enzymes but NOT Hexoseaminodose A. Without this enzyme they cannot break down Ganglioside GM2 proteins from the cell causing the build up of the ganglioside in the lysosome and clogs the cell
The residual vacuoles accumulate since the GM2 cannot be digested, and no exocytosis occurs (cell waste disposal system is destroyed) leading to death of cell, and death of patient.
What controls the degradation of Ganglioside GM2. Where does this usually occur?
The Tay-Sachs gene (HEXA) controls the degradation of Ganglioside GM2
-Tay-Sachs disease affects the HEXA Gene, which encodes beta-hexosaminidase A
This protein acts in lysosomes to break down ganglioside GM2
-The accumulation of GM2 (when enzyme not available) kills neurons. Neurons are necessary for life
this problem (no enzyme, causing lysosome to swell and not function properly–> killing neurons) usually occurs in nerve cells.
