Lecture 19: Autosomal dominant and recessive disorders Flashcards
What is a compound heterozygote?
Two recessive mutations that inhibit function
What is halpoinsufficiency?
One allele doesnt produce protein therefore overall protein isnt enough -> phenotype
What rules apply to autosomal dominance conditions when full penetrance?
- Affects either sex
- Transmitted by either sex
- (vertical transmission)
- 50% kids receive
What are the two examples of autosomal dominant conditions?
- Achondroplasia
- Marfan syndrome
What is achondroplasia? whats the mutation and presentation?
- Autosomal dominant
- No cartilage formation
- Shortened limbs, prominent forehead, depressed nasal bridge
- Mutation in the fibroblast growth factor receptor 3 (FGFR3)
What does the mutation in FGFR3 mutation in achondroplasia result in?
- Mutations result in premature differentiation of chondrocytes into bone (gain of function)
- Wild type allele cannot compensate / reduce the mutant allele activity
- Potential for prenatal diagnosis
Whats responsible for 80% of achondroplasia cases?
New mutations in the male germ line are responsible for 80% cases of achondroplasia.
De novo mutation in fathers germ line cells, increased risk with age
Why does paternal age impact chances of achondroplasia?
- Possibly germline selection
- Germline cells with FGFR3 mutation may have increased RAS/MAPK and PI3K/AKT pathway activation = weal proliferative advantage
What is marfan syndrome?
- Mutation in fibrillin-1, this binds to and disables any normal fibrillin (a dominant negative effect)
= Excessive elasticity of of fibrin - Several 100 alleles (allele heterogeneity)
- Different features b/c of variable expressivity
What is common gene product of autosomal recessive inheritence?
Usually enzymes, if heterozygotic then usually sufficient protein for adequate function
What are some examples of autosomal recessive inheritance?
- Phenylketonuria (PKU)
- Haemochromatosis
What is PKU?
Autosomal recessive disorder due to deficiency in phenylalanine hydroxylase (need to convert phenylalanine to tyrosine)
= Phenylalanine accumulates in the blood
What are the symptoms of PKU?
Vomiting, convulsions and mental retardation without treatment
Whats the management of PKU?
Low phenylalanine diet..
Whats screened as part of the NZ newborn metabolic screening program?
- AA disorders including PKU
- CF
- Congenital hypothyroidism
and many more
What is hereditary haemochromatosis?
Autosomal recessive disorder of iron metabolism
- Iron overload in tissues
- multi-organ dysfunction due to iron deposition
Note: Locus heterogeneity (many genes can lead to same phenotype)
b/c
- Increased iron absorption
- Excess iron accumulation
Whats the rate of heamochromatosis and age of onset?
1 in 10 caucasians
usually 40+
Whats the clincal features of heamochromatosis?
- Lethargy
- Organ damage as iron overloads
- Hepatomeagly and cirrhosis
- diabetes
- arthritis
- cardiomyopathy
- hypoganadism and hypothyroidism
What mutations lead to haemochromatosis?
Locus heterogeneity leads to hereditary haemochromatosis
Whats the impact of HFE gene discovery on clinical practice?
- Diagnosis now based on abnormal iron studies and HFE gene testing
- Liver biopsy only if HFE negative or concern of cirrhosis
- Can facilitate family screening
Summarise autosomal dominant disorders;
- 4000+ known
- Most are uncommon
- Tend to be more biologically complex than recessive
- Genetic products usually a non-enzymatic and diffusible protein
Summarise autosomal recessive disorders;
- Largest of single gene disorder
- Genes responsible on chromosomes 1-22
- Homozygous i.e both alleles recessive
- Gene product commonly an enzyme or diffusible protein
