Genetic Diseases: CF, PKU, & other single-gene defects

Question 1

inborn errors of metabolism

Answer 1

• pioneered by Archibald Edward Garrod, English physician
• discovered alkaptonuria in 1902
• presented work in 1908 to RCP
• added genes to germs and nutrition as a cause of disease
• “one gene, one enzyme” hypothesis
  
  • described recessive inheritance of many enzyme defects
  • no longer applicable but impressive for the time

Question 2

albinism

Answer 2

• lack of pigment due to defective tyrosinase
  
  • white hair, skin; red eyes
• pigment is created in melanocytes
• tyrosinase makes DOPA (dihydroxyphenylalanine)
  
  • without this first step, no pigment is produced
• melanin is a polymer of structures derived from tyrosine via tyrosinase
  
  • not a defined protein; varies by colour
• skin colour is an example of polygenic inheritance - many genes (40) influencing colour (also obesity for e.g.) –> tf no simple fix

Question 3

alcaptonuria

Answer 3

• Archibald Garrod, 1902
• darkening of urine from yellow to brown to black on exposure to air
• arthritis later in life
• deposition of brown pigment in joint cartilage and connective tissue
• defect of the tyrosine breakdown pathway

Question 4

cystinuria

Answer 4

• autosomal recessive inheritance
• formation of cysteine stones in the kidneys, ureter, and bladder
• mutations to a transporter protein in kidneys
• prevents reabsorption of basic or +ve AAs
  
  • cysteine tf becomes more concentrated in urine, forming cystinuria resulting in kidney stones

Question 5

cystic fibrosis

Answer 5

• 1/2500 births, 1/25 are carriers
• previous life expectancy ~20s, now ~30s
• affects:
  
  • respiratory system - lungs, buildup of mucous leading to repeated chest infections, lung damage, reduced function; persistent cough
  • digestive system - pancreas (blockage of duct), liver
  • reproductive system - sterility
• diagnosis:
  
  • Guthrie heel prick blood test for elevated immunoreactive trypsin produced by pancreas (~90% of cases)
  • indicated blood further tested for Phe 508 deletion
  • further confirmed by excessive NaCl in sweat
  • 11 common CF mutations in Victoria, 1900 mutations to CFTR known
    
    • CFTR: Cystic Fibrosis Transmembrane Conductance Regulator - CL channel protein active in membranes of the lungs, liver, pancreas, intestines, repro tract, and skin
    • located on chromosome 7
    • normal allele: 250 000bp, 27 exons
    • protein is 1480 AA long, 12 transmembrane segments
    • Phe 508 is part of normal Cl channel domain
    • w/o it, channel is blocked
      
      • Cl transportation essential for mucous clearing
      • Cl cannot be pumped out, mucous accumulates outside cell (in lungs primarily, also pancreatic duct)

Question 6

phenylketonuria (PKU)

Answer 6

• 1/14 000 Australians affected; 1/60 are carriers
• deficiency of phenylalanine hydroxylase
  
  • phenylalanine -/-> tyrosine; ++Phe
  • drives Phe -(aminotransferase)-> phenylpyruvate pathway
  • phenylpyruvate is a phenylketone, causes neurotransmitter pathway damage and also stops production of melanin from tyrosine (inhibits tyrosinase)
• identified by Dr. Asbjorn Folling, Norway 1934
• 1953 - low phenylalanine diet introduced as tx
  
  • if not introduced in first few weeks of life, PKU can cause mental retardation, seizures, tremors, and behavioural disorders
• 1960 - Guthrie test, dried spot of blood from a heel prick of newborns tested for phenylpyruvate and other abnormal metablism products of Val, Leu, Ile

Question 7

autosomal dominant

Answer 7

dominant allele expressed at a particular locus on any gene other than a sex chromosome

codes for a functional protein

e.g. Blue-Yellow colour blindness

Question 8

autosomal recessive

Answer 8

recessive allele is not expressed at a particular locus on any gene other than a sex chromosome

codes for a mutant, non-functional protein

Question 9

X-linked dominant

Answer 9

• dominant gene carried on the X chromosome
• less common than X-linked recessive
• do not affect males more than females

Question 10

X-linked recessive

Answer 10

• gene causing trait or disorder is on the X chromosome
• carrier females (one copy of the mutation) do not express phenotype
• expressed in males because they only have one X
• expressed in homozygous females (on both Xs)
• e.g. red-green colour blindness, male pattern baldness, hemophilia A, Duchenne muscular dystrophy, Lesh-Nyhan syndrome

Question 11

Y-linked

Answer 11

• determination of phenotype by an allele on Y
• few traits are Y-linked
• diseases are rare
• passed from father to son
• Y chromosome deletions are a genetic cause of male infertility

Question 12

Archibald Edward Garrod

Answer 12

• 1857-1936
• English physician
• pioneered field of inborn errors of metabolism
• studied albinism, alcaptonuria, cystinuria, congenital porphyrinuria, congenital steatorrhoea, and pentosuria

Question 13

The major burden of pathology in Australia from genetic disease is due to

Answer 13

Cystic Fibrosis

Question 14

What was the first disease to be routinely tested for at birth and treated as required?

Answer 14

phenylketonuria (PKU)

Question 15

What technique is commonly used in genetic testing?

Answer 15

PCR for gene amplification

Question 16

Single gene disorders can be inherited

Answer 16

• autosomal dominant
• autosomal recessive
• X-linked dominant
• X-linked recessive
• Y-linked
• mitochondrial

Question 17

What pathologies are linked to specific genes?

Answer 17

• colour blindness
• Duchenne muscular dystrophy
• haemochromatosis
• haemophilia
• neurofibromatosis
• polycystic kindey disease
• Prader-Willi syndrome
• sickle-cell disease
• Tay-Sachs disease