65 - CF, PKU, Other Common Single-Gene Defects

Question 1

Who pioneered the field of inborn metabolic errors

Answer 1

Archibald Edward Garrod

Question 2

Genetic disease with greatest disease burden in Australia

Answer 2

Cystic fibrosis

Question 3

First genetic disease to be tested for at birth, and treated.

Answer 3

Phenylketonuria

Question 4

Common technique involved in genetic testing

Answer 4

PCR

Question 5

Inheritance of gout

Answer 5

Autosomal dominant

Question 6

Disease where someone can’t recycle purines

Answer 6

Lesch-Nyhan

Question 7

Lesch-Nyhan

Answer 7

Genetic disease where patient can’t recycle purines.

Self-mutilate (eat nose, lips)

Question 8

Acromegaly

Answer 8

Grow very large, very prominent jaw.

From pituitary gland secreting GH into adulthood

Question 9

Syndrome with extreme flexibility

Answer 9

Ehlers Danlos syndrome (defect in collagen)

Question 10

Alkaptonuria
1)
2)
3)

Answer 10

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.

Question 11

Mendel’s first law

Answer 11

People have two copies of a gene for a characteristic

Question 12

Phenotype of Klinefelter’s syndrome

Answer 12

Male

Question 13

Example of a trait with incomplete dominance

Answer 13

Whether hair is straight, curly or wavy

Question 14

Mutations leading to colour blindness

Answer 14

Mutations in coneopsins or rhodopsins.

Short-, medium and long-wavelength genes.

Question 15

Inheritance pattern of the most common red-green colourblindness

Answer 15

X-linked recessive

Question 16

Examples of X-linked recessive conditions
1)
2)
3)
4)

Answer 16

1) Duchenne muscular dystrophy
2) Haemophilia A
3) Leisch-Nyhan syndrome
4) Male pattern baldness

Question 17

Mendel’s second law

Answer 17

Different characteristics are inherited independently

Question 18

Difference between congenital and genetic conditions

Answer 18

Congenital is a condition present at birth, that doesn’t have to have a genetic basis, EG: (S)-thalidomide

Question 19

Phenylketanuria prevalence

Answer 19

1/14,000 births in Australia.

1/60 are carriers

Question 20

Effect of not treating PKU in first few weeks of life 
1)
2) 
3)
4)

Answer 20

1) Mental retardation
2) Seizures
3) Tremors
4) Behavioural defects

Question 21

Test for PKU at birth

Answer 21

Guthrie test.

Heel prick gives blood, which is tested for phenylpyruvate

Question 22

What causes PKU?

Answer 22

Lack of phenylalanine hydroxylase.

Question 23

Result of lacking phenylalanine hydroxylase

Answer 23

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

Question 24

Why can PKU children be blonde, even without blonde parents?

Answer 24

PKU causes phenylpyruvate buildup, which can inhibit tyrosinase, which makes melanin

Question 25

CF prevalence in Australia

Answer 25

1/2,500 live births

Question 26

How is CF diagnosed at birth?

Answer 26

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)

Question 27

Most common defect leading to CF

Answer 27

Delta F508

Question 28

Chromosome where CFTR is

Answer 28

Chromosome 7

Question 29

CFTR size

Answer 29

Cystic fibrosis transmembrane conductance regulator is 250, 000bp, with 27 exons.
Protein is 168,173 daltons.

Question 30

Amino acid profile of human skin

Answer 30

33% glycine
22.2% proline
11% alanine

Question 31

Why does human skin have the amino acid profile 33% glycine, 22.2% proline and 11% alanine?

Answer 31

Sequence of most collagens involves the repeating sequence Gly-Pro-Ala

Question 32

What do glycines do in collagen?

Answer 32

Point to the middle of the tri-helix.

Question 33

Disease where glycine is no longer stacked in the middle of a collagen trihelix

Answer 33

Osteogenesis imperfecta

Question 34

Osteogenesis imperfecta

Answer 34

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

Question 35

Ehlers-Danlos syndrome prevalence

Answer 35

1 in 10,000

Question 36

Syndrome involving bone overgrowth, joint laxity, excessively long extremities for the trunk

Answer 36

Marfan syndrome

Question 37

Marfan syndrome

Answer 37

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.

Question 38

Gene deficiency leading to albinism

Answer 38

Tyrosinase (can’t produce melanin)

Question 39

Role of tyrosinase

Answer 39

Makes DOPA (dihydroxyphenylalanine).
Melanin is a derivative of these structures.

Question 40

Number of Hb variants known

Answer 40

Over 800

Question 41

Effect of most Hb variants

Answer 41

Silent.

Question 42

Point mutation leading to sickle cell anaemia

Answer 42

CTT changed to CAT, which results in a valine instead of a glutamic acid.

Question 43

Effect of glutamic acid -> valine change in Hb beta chain

Answer 43

Sickle-cell anaemia

Valine is hydrophobic, binds to a hydrophobic pocket present on deoxyhaemoglobin, forms insoluble aggregates.

Question 44

Porphyria

Answer 44

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