Lecture 15 -Autosomal Dominant and Recessive Disorders

Question 1

Autosomal Dominant

Answer 1

-only need one mutated allele from either parent
affects both sexes and is transmitted by either sex
-child of affect has 50% chance of developing disorder
-Many known disorders, but most of these are uncommon
-tend to be more biologically complex then AR

-the 50% of the mutated protein has to overwhelm the normal 50%.

Question 2

Autosomal recessive

Answer 2

• affected people usually have unaffected CARRIER parents
• affects/is transmitted by both sexes
• risk increased if parents related
• 25% chance of being affects

Question 3

Autosomal dominant disorders usually affect a non-enzymatic and non-diffusible protein. Why?

Answer 3

Because is the normal 50% of protein was diffusible and enzymatic it’d be much harder for the mutant 50% to dominant.
This is why many AD disorders are uncommon.

Question 4

Achondroplasia

Clinical Features

Answer 4

AD dominant 'dwarfism'
-altered ossification of cartilage to bone.
-Most common form of dwarfism
CF:
-shortening of limbs
-prominent forehead
-depressed nasal bridge
-otitis media

Question 5

Cause of Achondroplasia. What does this do

Answer 5

Mutation in the Fibroblast Growth Factor Receptor 3 gene
Means there is premature differentiation of chondrocytes > bone and the wildtype allele can’t compensate
-likelihood increases with PAternal age

Question 6

Why does achondroplasia increase with paternal age?

Answer 6

80% sufferers have ‘Normal’ parents, for these people a spontaneous ‘de novo’ mutation has occurred in the fathers germ cells.
These mutations are far more common in older men.

This is bc the mutation affects downstream signalling pathways, the mutated FGFR3 gene spermatogonial stem cells get an growth advantage, they accumulate….

NOTE** 20% of achondroplasia follows the normal AD disorder pattern of 50% offspring if one parents is affected

Question 7

Marfans Syndrome

Answer 7

AD disorder
Tall, skinny
mutant protein (mutated fibrillin-1 gene) binds to and disables normal fibrillin
‘Dominant negative effect’
There are several hundred mutant alleles = allelic heterogeneity

Question 8

• Gene product can be anything (enzyme or diffusible)
• Gene responsible of chromosome 1-22
• Largest group of single gene disorders

What disorder is this? Give me two examples

Answer 8

Autosomal Recessive Disorder

eg) Phenylketonuria (PKU), Cystic Fibrosis (CF), haemocromotosis

Question 9

Phenylketonure (PKU)

Answer 9

AR disorder

• inherited metabolic defect.
• Mutation of ‘phenylalanine hydroxylase’ that usually convert phenylalanine > tyrosine.
• Phenylalanine accumulates > vomiting, convulsion and mental retardation.
• carrier frequency 1 in 50
• allelic heterogeneity.

Treatment: low phenylalanine diet (hard to do)

Question 10

What is the difficulty of allelic heterogeneity (several different mutations on the gene can cause the disorder)

Answer 10

It can make it extremely hard to screen for

Question 11

Locus heterogeneity/ types of haemochromotosis

Answer 11

Type 1 (classical) HFE mutation of two (C282Y) or (H63D) = 95%

non-classical types
Type 2 juvenile haemochromotosis (2 genes HJV and HAMP mutated)

Type 3 haemochromotosis due to ferroportin gene

ALL AUTOSOMAL RECESSIVE

Question 12

Phenylketonure (PKU)

Answer 12

AR disorder

• inherited metabolic defect.
• Mutation of ‘phenylalanine hydroxylase’ that usually convert phenylalanine > tyrosine.
• Phenylalanine accumulates > vomiting, convulsion and mental retardation.
• carrier frequency 1 in 50
• allelic heterogeneity.

Treatment: low phenylalanine diet (hard to do)

Question 13

What is the difficulty of allelic heterogeneity (several different mutations on the gene can cause the disorder)

Answer 13

It can make it extremely hard to screen for

Question 14

Haemochromatosis. What is it, some main clinical feature are?

Answer 14

Autosomal recessive disorder

• increased iron absorption > iron overload > tissue/organ damage.
• 1/10 carriers, 1/400 homozygous
• Late onset as damage build up over time
• M= F (males present earlier as women lose blood in menstruation)

CF:

• lethargy
• organ damage cirrhosis, arthrisis, diabetes

BUT the phenotype varies

Question 15

Locus heterogeneity/ types of haemochromotosis

Answer 15

Type 1 (classical) HFE mutation of two (C282Y) or (H63D)

non-classical types
Type 2 juvenile haemochromotosis (2 genes mutated)

Type 3 haemochromotosis due to ferroportin gene

ALL AUTOSOMAL RECESSIVE

Question 16

HFE mutation cause haemochromotosis by…

Answer 16

90% have a mutation in the Cys282Tyr (homozygous)

5% ‘compound heterozygotes’ of Cys282Tyr and His63Asp, one mutation from each parent

Question 17

Diagnosis of haemochromotosis

Answer 17

Based on abnormal iron studies and HFE gene testing (as there is only a few genes that can cause this)

Liver biopsy done is previous testing is negative or if there is concern about hepatocellular carcinoma