Autosomal dominant and recessive disorders

Question 1

Are autosomal dominant inherited genes common or rare? Name two examples of autosomal dominant conditions.

Answer 1

Relatively uncommon as they are very complex disorders.

Achondroplasia, Marfan syndrome and Huntingtons disease

Question 2

What are de novo (new) mutations?

Answer 2

De novo mutation, an alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell (egg or sperm) of one of the parents or in the fertilized egg itself.

Question 3

Describe the autosomal condition called Achondroplasia. What causes an increase of incidence of this condition.

Answer 3

Achondroplasia (a form of dwarfism)
- a mutation in one of the fibroblast growth factor receptor genes that results in abnormal (premature) ossification of cartilage into bone. (the normal allele inhibits excessive growth).

• there is increasing incidence with increasing paternal age as there is something to do with the sperm. It is thought that the spermatogonial stem cells that have the mutation have an advantage as they can grow faster due to faster pathways in the cell.

Question 4

Describe the autosomal condition called Marfan Syndrome.

Answer 4

Marfan Syndrome
- a mutation in the fibrillin-1 gene that results in a dominant negative effect. (the mutated allele binds to and disables the normal fibrillin). This leads to excessive elasticity of fibrillin.

Features of the disease:
Allelic heterogeneity
- there are several alleles for the same gene that when mutated will produce the same effect

Pleiotropy
- it can effect severa different organ systems

Varibale expressivity
- different features may be evident in different members of the same family

Question 5

Autosomal recessive conditions are more common in consanguineous relationships, what does this mean?

Answer 5

More common in relationships where the parents are related (incest).

Question 6

Why are autosomal recessive conditions usually not going to affect the individual if they are heterozygous (one dominant/functional allele and one recessive/mutated allele)

Answer 6

If the allele is coding for a protein for example then the 50% of the protein that is still functional is adequate to produce normal function.

Question 7

Describe the autosomal recessive disorder called Phenylketonuria (PKU)

Answer 7

Phenylketonuria
- due to a deficiency in Phenylalanine hydroxylase which is necessary for conversion of phenylalanine to tyrosine. If pheylalanine builds up in the blood then it can cause vomiting, convulsions and mental retardation.

• it is very hard to screen for as there is allelic heterogeneity (there are over 450 alleles that could be responsible), but it is screened for in a newborn heel prick test
• the management is to put the baby on a low phenylalanine diet

Question 8

Describe the autosomal recessive disorder called Haemocromatosis

Answer 8

Haemocromatosis
- results in an iron overload due to increase absorption of iron from the digestive tract. Haemocromatosis is thought to be due to a mutation of a protein which regulates transfferin and so without this protein there is no control over how much iron is taken up. Hence the histological features are that there is raised serum ferritin (iron in the blood) and raised transferrrin saturation.

• In 90% of people it is due to a mutation called C282Y on the the HFE gene of chromosome 6
• In 5% of patient they have both the C282Y mutation and another known mutation called H63D both to the HFE gene
• Haemocromatosis is also known to have locus heterogeneity as there have been other gene mutations indentified that cause the condition
• Treating this condition is fairly easy as it just requires the individual to be “bled off” every few weeks to months to remove the excess iron in the blood. Failure to treat however will result in organ damage - particularly the liver which may lead to cirrhosis and increased risk of hepatocellular carcinoma