65 - CF, PKU, Other Common Single-Gene Defects Flashcards
Who pioneered the field of inborn metabolic errors
Archibald Edward Garrod
Genetic disease with greatest disease burden in Australia
Cystic fibrosis
First genetic disease to be tested for at birth, and treated.
Phenylketonuria
Common technique involved in genetic testing
PCR
Inheritance of gout
Autosomal dominant
Disease where someone can’t recycle purines
Lesch-Nyhan
Lesch-Nyhan
Genetic disease where patient can’t recycle purines.
Self-mutilate (eat nose, lips)
Acromegaly
Grow very large, very prominent jaw.
From pituitary gland secreting GH into adulthood
Syndrome with extreme flexibility
Ehlers Danlos syndrome (defect in collagen)
Alkaptonuria
1)
2)
3)
1) Lack of homogentisic dioxygenase. Can’t break down toxic homogentisic acid.
2) Darkening of urine from yellow to black after exposed to air
3) Develop arthritis later in life, characterised by deposition of brown pigment in joint cartilage and connective tissue.
Mendel’s first law
People have two copies of a gene for a characteristic
Phenotype of Klinefelter’s syndrome
Male
Example of a trait with incomplete dominance
Whether hair is straight, curly or wavy
Mutations leading to colour blindness
Mutations in coneopsins or rhodopsins.
Short-, medium and long-wavelength genes.
Inheritance pattern of the most common red-green colourblindness
X-linked recessive
Examples of X-linked recessive conditions 1) 2) 3) 4)
1) Duchenne muscular dystrophy
2) Haemophilia A
3) Leisch-Nyhan syndrome
4) Male pattern baldness
Mendel’s second law
Different characteristics are inherited independently
Difference between congenital and genetic conditions
Congenital is a condition present at birth, that doesn’t have to have a genetic basis, EG: (S)-thalidomide
Phenylketanuria prevalence
1/14,000 births in Australia.
1/60 are carriers
Effect of not treating PKU in first few weeks of life 1) 2) 3) 4)
1) Mental retardation
2) Seizures
3) Tremors
4) Behavioural defects
Test for PKU at birth
Guthrie test.
Heel prick gives blood, which is tested for phenylpyruvate
What causes PKU?
Lack of phenylalanine hydroxylase.
Result of lacking phenylalanine hydroxylase
Body can’t convert phenylalanine to tyrosine.
This drives conversion of phenylalanine to phenylpyruvate, which builds up in the brain, causing brain damage.
Inhibits tyrosinase, which can make melanin
Why can PKU children be blonde, even without blonde parents?
PKU causes phenylpyruvate buildup, which can inhibit tyrosinase, which makes melanin
CF prevalence in Australia
1/2,500 live births
How is CF diagnosed at birth?
Guthrie test (heel prick), testing for elevated immunoreactive trypsin (secreted by the pancreas). This detects ~90% of CF cases.
Diagnosed with sweat test (elevated NaCl–>CF)
Most common defect leading to CF
Delta F508
Chromosome where CFTR is
Chromosome 7
CFTR size
Cystic fibrosis transmembrane conductance regulator is 250, 000bp, with 27 exons.
Protein is 168,173 daltons.
Amino acid profile of human skin
33% glycine
22.2% proline
11% alanine
Why does human skin have the amino acid profile 33% glycine, 22.2% proline and 11% alanine?
Sequence of most collagens involves the repeating sequence Gly-Pro-Ala
What do glycines do in collagen?
Point to the middle of the tri-helix.
Disease where glycine is no longer stacked in the middle of a collagen trihelix
Osteogenesis imperfecta
Osteogenesis imperfecta
Glycine at position 748 of collagen gene mutates to cysteine.
Glycine no longer stacks in middle of the trihelix, interfering with strand alignment.
Main symptom is brittle bones
Ehlers-Danlos syndrome prevalence
1 in 10,000
Syndrome involving bone overgrowth, joint laxity, excessively long extremities for the trunk
Marfan syndrome
Marfan syndrome
Fibrillin 1 gene (FBN1) is mutated.
Fibrillin no longer deposited in ECM, no longer helps build microfibrils, which become part of elastic fibres.
Bone overgrowth, joint laxity, excessively long extremities proportional to the trunk.
Gene deficiency leading to albinism
Tyrosinase (can’t produce melanin)
Role of tyrosinase
Makes DOPA (dihydroxyphenylalanine). Melanin is a derivative of these structures.
Number of Hb variants known
Over 800
Effect of most Hb variants
Silent.
Point mutation leading to sickle cell anaemia
CTT changed to CAT, which results in a valine instead of a glutamic acid.
Effect of glutamic acid -> valine change in Hb beta chain
Sickle-cell anaemia
Valine is hydrophobic, binds to a hydrophobic pocket present on deoxyhaemoglobin, forms insoluble aggregates.
Porphyria
Mutation in gene of one of the enzymes involved in converting delta-aminolevulinate to haem (porphyrin metabolism).
Leads to loss of haem negative feedback (as haem isn’t being produced).
Buildup can cause photosensitivity, neuropathy, abdominal pain, paleness
