Single Gene Disorders

• What are single gene disorders caused by?

  point mutations
• What are the issues with single gene disorders?

  high morbidity and mortality in children

  Most are incurable
• Describe an autosomal recessive condition:

  Phenotype apparent only in individuals homozygous for disease allele

  • heterozygoud parents are unaffected (carriers)
  • complete loss of gene function leads to phenotype
• Describe autosomal dominant conditions:

  • partial loss of gene function (haploinsufficiency) lead to phenotype e.g Familial Hypercholesterolaemia
  • Toxic protein interferes with cell function e.g Huntingtons
• what does consanguinity mean?

  sexual relationship with a blood relative
• Describe cystic fibrosis:

  • Autosomal recessive
  • Carrier frequency is 1 in 25
  • if untreated sufferers die before their 5th birthday but now life can be extended into adulthood
• symptoms of Cystic fibrosis:

  • accumulation of mucus in lungs, pancreas, digestive tract and other organs
  • multiple effects including, chronic bronchitis, recurrent bacterial infections
• what doe sth CF gene code for?

  CFTR - cystic fibrosis transmembrane conductance regulator

  • regulates the flow of Cl- across the membrane
• what is the most common mutation causing cystic fibrosis?

  ΔF508
• Describe the ΔF508 mutation?

  deletion of 3 base pairs results in loss of a Phe residue at position 508

  protein does not fold normally and is more quickly degraded

  there are >800 different CFTR mutations that cause cystic fibrosis
• How does defect in CFTR cause CF?

  defect in Cl- transport causes extracellular mucus to become thicker and stickier

  Treatment: life is prolonged by antibiotics and by daily massage to clear mucus from airways
• What are medicine for cystic fibrosis?

  Drugs to improve function of mutated protein

  gene therapy
• Describe drugs to improve function of mutated protein:

  • gating mutation can be treated with the drugs that helps open gates
  • Other mutation can be treated with combination therapies that bring more of the chloride channels to the surface and help those channels to operate more effectively
• Describe Gene therapy:

  • gene therapy treatments: to provide patients with a copy of the correct chloride channel
  • Clinical trials for integrating and non-integrating gene therapies are underway
• What are the symptoms of sickle cell anaemia?

  Anaemia

  joint pain

  swollen spleen

  frequent severe infection
• What is the treatment of sickle cell anaemia?

  Regular blood transfusion
• What is the cure of sickle cell anaemia?

  bone marrow transplanr
• what does pleiotropic effect mean?

  One gene influencing multiple traits.
• what is caused by sickle cell anaemia?

  mutation in the gene for beta chain of haemoglobin, leads to incorrect folding of the protein

  Defective haemoglobin forms long chains rigid polymers (after O2 is release) which deform the red blood cell
• Heterozygotes also have a phenotype in low oxygen conditions
• How does heterozyogote lead to an advantage of sickle cell?

  sickle cell trait confers resistance to malaria - an example of heterozygote advanatge
• What are the symptoms of Huntingtons disease?


  Jerky movements

  personality changes

  deterioration of walking, speaking and swallowing abilities

  death will result from complucation such as choking, infection or heart failure
• Huntingtons disease is a late-onset
• what is the molecular cause of huntingtons?

  large gene mapping studies defects on chromosome 4

  narrowed down to abnormalities in the Huntington's

  • Gene contains CAG repeats (encoding glutamine) 11-34 repeats = normal
  • 36-125 repeat = huntington disease
• What are the symptoms of familia hypercholesterolaemia?


  high levels of cholesterol in the blood from an early age

  cholesterol deposits build up in joints

  cardiovascular disease
• what is the treatment of familial hypercholesterolaemia?

  Cholesterol-lowering drugs e.g statins

  low cholesterol diet
• What is familia hypercholesterolaemia due to?

  Lack of low density lipoprotein receptor
• FH: without LDL receptor the cholesterol accumulates in the blood.
• FH is an example of incomplete dominance
• what does homozygote in FH lead to 6-fold increase in blood cholesterol - heart attacks at age of 2
• what does heterozygote in FH lead to?

  2-fold increase in blood cholesterol - heart attacks by age of 35
• FH: dominant phenotype is caused by haploinsufficiency
• what is a genetic disorder in queen victorias family?

  haemophilia B
• describe Duchenne muscular dystrophy

  • Xp21.2
  • muscle wasting disease
  • The most frequent lethal childhood genetic disease (1 in 3500 males)
  • affected gene codes for a muscle protein called dystrophin
  • dystrophin gene is very large (2.6 million bp) make it prone to rearrangements
• what is dystrophin?

  A part of a protein complex that connects the cytoskeleton of a muscle fibre to the surrounding extracelluar matrix through the cell membrane.
• what occurs Duchenne muscular dystrophy?


  Muscles in affected males progressively die. Death occur by age 20 from respiratory or cardiac failure.
• What is the treatment of duchenne muscular dystrophy?

  Currently incurable although there are promising gene therapy techniques under research to replace a normal copy of dystrophin