Molecular,Biochem,Cellular Basis of Genetics (Ch.12) Flashcards
What are the 2 classes of proteins?
- Housekeeping Proteins
- Tissue-Specific Specialty Proteins
What are houskeeping proteins?
They are fundamental to maintenance of structure and function
What are tissue-specific specialty proteins?
have unique functions
Where do tissue-specific specialty proteins get made?
In 1 or different cells
Where do we find houskeeping genes?
in every cell
What are the two broad generalizations that can be made about the site of a disease and the site of a proteins expression?
- A mutation in a tissue-specific protein produces a disease restricted to that tissue
- housekeeping genes are in all cells; but a mutation in one will not cause all others to express pathologically.
What are the 2 reasons why clinical effects of mutations in housekeeping proteins are frequently limited to one or a few tissues?
- Genetic redundancy
- A specific tissue may be affected because the protein in question is expressed abundantly there and serves a specialty function
How do you explain clinical heterogeneity of genetic disease using genetic variation?
- allelic heterogeneity-mutation:
* different alleles of a single gene can be compared with phenotypes of variable severity - locus heterogeneity-mutation:
* A mutation in a different gene can cause a similar but distinguishible phenotype. - Modifier genes:
* mutations in a separate gene causes the same mutation in another gene to have different effects.
What is Phenylketonuria (PKU)?
Is an inherited error in metabolism caused by deficiency in Phenylalanine hydroxase (PAH). (Phenylalanine builds up)
What symptoms can be seen in loss of Phenylalanine hydroxylase?
- mental retardation
- organ damage
- unusual posture
- Musky odor in diaper from Phenylpyruvic Acid
Classic PKU is what kind of inheritance?
Autosoma Recessive
How many alleles are mutated in the PAH gene in PKU?
both alleles are mutated in chromosome 12
the one with more milder phenotype predominates
What does Phenylalanine hydroxylase do in the body?
converts phenylalanine to tyrosine by hydroxilating the phenolic ring
What is the mild form of PKU?
hyperphenylalanemia
Apart from PAH, what do the other 4 genes that cause PKU do?
production or recycling of tetrahydrobiopterin (BH4)
What is the normal plasma level of phenylalanine?
<1 mM (1 mg/dl)
What does BH4 do with PAH?
Its a cofactor for:
Tyrosine —–> Cathecolamine ——-> NE & Epinephrin
Tryptophan ——-> 5-HT (Serotonin)
What do BH4-deficient patients develop?
profound neurological problems
What is BH4 used for?
it is a cofactor for PAH
it is a cofactor for Tryptophan hydroxylase and tyrosene hydroxilase
Tyrosine————–>Catecholaminas————-> NE & E
Tryptophan —————–> 5-HT(Serotonin)
True of False
Patients with PKU are usually homozygotes?
False - compound heterozygotes
What are the Clinical Features of PKU?
- developmental delay in infancy
- microcephaly
- seizures
- hyperactivity
- behavioral disturbances
- musky smell in diaper (phenylalanine metabolized to phenylperuvic acid which is peed)
How do you treat PKU?
phenylalanine diets (avoid proteins, dairy & eggs) and supplements of BH4
What happens if PKU is left untreated?
Severe Mental Retardation
What is Maternal Phenylketonuria?
It is a type of PKU that affects the unborn child
It attacks the developing CNS
What are the symptoms of Maternal Phenylketonuria?
- microcephaly
- mental retardation
- heart malformations
- growth impairment
What type of inheritance do most of the Lysosomal diseases have?
Autosomal Recessive
What is the treatment of lysosomal storage disease?
ERT: Enzyme Replacement Therapy
What happens with lysosomes in lysosomal storage disease?
They accumulate substrate inside lysosome and it leads to cellular dysfunction and cell death.
What kind of disease is Tay-Sachs?
Lysosomal Storage Disease
What kind of disease is Gauchers Disease?
Lysosomal Storage Disease
What kind of disease is MPS I (Mucopolysaccharidoses) disease?
Lysosomal Storage Disease
Type I = Hurler’s
What kind of disease is MPS II (Mucopolysaccharidoses) disease?
Lysosomal Storage Disease
Type II = Hunters
What is another name for MPS I (Mucopolysaccharidoses) disease?
Hurler’s
What other name does MPS II (Mucopolysaccharidoses) disease have?
Hunter’s
What is happening with Tay Sachs disease?
Lysosomes cannot degrade GM2 Gangliosides
What enzyme is deficient in Tay Sachs?
Ubuquitous Hexosaminidase A Enzyme
With what type of inheritance is ubiquitous hexosaminidase A enzyme related?
with Autosomal Recessive inheritance
What body part is mainly affected clinically with Tay Sachs?
The brain since it is the predominant site of GM2 ganglioside synthesis
What are the 3 components of the acitive Hex A enzyme?
- HexA
- HexB
- Sandoff activator protein
What disease symptoms are clinically identical to Tay Sachs?
Sandhoff disease
Hex A needs Sandhoff Activator Protein thus if absent, identical symptoms of Tay Sach are to be seen.
What does the activator protein of the HexA enzyme do?
binds the ganglioside substrate and present it to the enzyme. NANA (N-acetyl neuraminic acid)
If there is a 4-base insertion on HexA, what kind of mutation is present? and what are the bases and where are they located?
A frameshift mutation. TATC insertion on Exon 11
In what population will we see Tay Sachsm more predominantly?
In Ashkenazi Jews as usual
What will not be made if there is a 4-base insertion/frameshift?
HexA will not be made
In Tay Sachs, when will infants begin to show signs of the disease?
first 3-6 months they look normal, afterwards they show signs of neurological deterioration. Usually death @ 2-4yrs
What is a cherry red spot in the retina a sign off? and what disease presents with this symptom?
Tay Sachs and it means that there is accumulation of storage material in the retina
Later onset of Tay Sach variants will manifest with these symptoms…
- Lower motor neuron dysfunction
- Ataxia
These occur because of spinocerebellar degeneration
- Psychosis in 1/3 of patients
Later onset variants will manifest with symtoms except for?
vision and Intelligence that will remain normal
Where do GAG’s or Mucopolissaccharide chains accumulate?
Lysosome
What are GAG’s made off?
Long dissacharide repeating chains with two sugar molecules
GAG’s or Mucopolysaccharide Disorders accumulate in lysosomes of tissues and cause what type of deformities?
Skeletal and extracellular matrix deformities
What type of inheritance is Hurler’s Syndrome?
Autosomal Recessive (its lysosomal)
What is deficient in Hurler’s Syndrome?
alpha-L-iduronidase
How does Hurler’s present?
- corneal clouding
- skeletal abnormalities
- death by cardiorespiratory failure
- by 3 years there is linear growth
- hearing loss
- profound mental retardation
- coarse facies
Rule of L: HurLe’s, alpha-L-iduronidae, corneaL cLouding, hearing Loss
What is I-Cell disease?
Lysosomal storage disease
Defect in enzyme that transfers phosphate group to mannose residues *in the Golgi*.
or…in fancy world:
“There is a N-acetylglucosamine-1-phosphotransferase deficiency leading to deficiency in protein trafficking”.
How do patients with I-Cell present?
unusual facial features
skeletal changes
Mental retardation
excess acid hydrolases in body fluids
What is Classic Homocystinuria?
Mainly it is a deficiency in enzyme cystathionine ß-synthase (Vit. B-6)
can also occur with deficiency of methionine synthase (folate = Vit. B-12)
What inheritance is Homocystinuria?
Autosomal Recessive
What are some of the symptoms that patients with homocystinuria will present with?
mental retardation
osteoporosis of long bones
Dislocation of the Lens
thromboembolism of the veins & arteries
6 causes of homocystinuria
Classic = defective cystathionine synthase
decrease in Methyl-H4-folate reductase: impairing methionine synthase
defects in the intracellular metabolism of cobalamins lead to a secondary decrease in the synthesis of methyl-cobalamin (methyl-B12) and thus in the function of methionine synthase.
Defect in cobalamine absorption and transportation
What is alpha-1-antitrypsin deficiency?
deficiency in a1AT secreted by the liver into plasma. It inhbits elastase
(the function of elastase is to degrade alveolar walls causing COPD)
Elastase is secreted by neutrophil in the respiratory track
What type of inheritance is alpha-1-antitrypsin deficiency?
Autosomal Recessive
What happens with the Z allele in alpha-1-antitrypsin deficiency?
it is the most common
What do homozygotes with Z/Z in alpha-1-antitrypsin deficiency develop?
17% develop neonatal jaundice & 20% of those will develop cirrhosis
With what does the Z protein tend to aggregate with?
aggregates with the RER of hepatocytes which causes formation of bead-like necklaces of mutant alpha-1-antitrypsin polymers.
It results in increased elastase activity in lungs (alveoli elastin loss)
What is the effect of smoking in alpha-1-antitrypsin?
It oxidizes methionine causing a decrease in affinity of alpha-1-antitrypsin for elastase by 2,000 folds.
What type of disease is I-Cell?
Lysosomal storage disease
