COD Genetic diseases

Question 1

What are the 3 types of mutation

Answer 1

Deletions
Insertions
Single base substitutions

Question 2

What is a missense mutation

Answer 2

aa replaced with a different aa

Question 3

What is a nonsense mutation

Answer 3

aa codon replaced replaced with a stop codon

Question 4

What are splice shifts?

Answer 4

Intron/exon splice sites are lost or created

Question 5

What can deletions and insertions cause?

Answer 5

Frameshift mutations

May alter the reading frame

Question 6

What are the 4 main effects of different types of mutations?

Answer 6

Loss of function mutation
Gain of function mutation
Dominant negative mutation
Mutations that affect gene dosage

Question 7

Describe a loss of function mutation

Answer 7

A gene product that has reduced or none of it function
Any mutation that inactivates a gene product will result in the same clinical symptoms
eg Duchenne Muscular Dystrophy (DMD)

Question 8

Describe DMD

Answer 8

Loss of function
Progressive muscular weakness
Mostly males affected
Occurs in families (1 in 3500 male births)
No treatment
X-Linked disorder, mendelian inheritance, recessive
Severe clinical symptoms- no detachable dystrophin expression
60% patients have deletions

Question 9

Describe a gain of function mutation

Answer 9

A gene product that has required a new, abnormal function
Only the specific mutation that gives the product its new function will result in the clinical phenotype
eg Huntington’s disease

Question 10

Describe Huntington’s disease

Answer 10

It is a triplet expansion
Mutation occurs as expansion of an unstable CAG repeat within the coding gene sequence for the protein huntingtin
Disease occurs when the number of repeats exceeds 35
The greater the number of repeats the earlier the age of onset
The mutated allele is transcribed and translated.
Late onset, neurodegenerative, lethal disorder, dominant
Death of medium spiny neurons in striatum
Motor, emotional & cognitive symptoms
Death within 15-20 years

Question 11

What are trinucleotide repeat diseases? Use the Huntingtin gene as an example

Answer 11

Expanded and unstable CAG repeat in exon 1 of the (huntingtin) HTT gene
Normal alleles are 9-35 CAG repeats
Affected alleles are 36-100 CAG repeats
The CAG repeat encodes a polyglutamine tract in the protein.
Polyglutamine tract causes the protein to aggregate causing neuronal cell death.
Protein aggregation - common in the pathology of CAG repeat diseases, Alzheimer disease, Parkinson disease and the prion diseases

Question 12

Describe a dominant negative mutation

Answer 12

Mutant gene loses its own function and also prevents other gene products from functioning correctly
Common where the mutation affects a multimeric protein encoded by more than one gene
eg: Osteogenesis Imperfecta
Mutations in Type I collagen have a dominant negative effect

Question 13

Describe Osteogenesis Imperfecta

Answer 13

very mild (bone weakness, blue sclerae, slight hearing loss)
lethal (ribs too weak to support breathing at birth)
Type I collagen is a major protein constituent of bone
exists as a triple helix (2 a1 and 1 a2 chains)
encoded by 2 different genes - COL1A1 & COL1A2
mild phenotype - the mutated alpha chain is excluded from Type I collagen
lethal phenotype - the mutated alpha chain is incorporated into Type I collagen
The effect of the mutation is enhanced due to the mutated chain interfering with the function of the normal alpha chains

Question 14

Describe gene dosage effects

Answer 14

The mutation varies level of gene dosage
The effect depends upon gene and cell type
eg: Downs Syndrome - extra (but normal) chromosome 21
Lethal phenotype associated with 50% increase in dosage of chromosome 21

Question 15

Define hemizygous

Answer 15

Humans are diploid for autosomes and X chromosome in females, but the sex chromosomes, X and Y are very different in structure and gene content
Females have 2 alleles for X chromosome, can be homozygote or heterozygote for any locus on X chromosome
Males have only one allele for X and one allele for Y chromosomes, therefore are hemizygous

Question 16

What is autosomal dominant inheritance?

Answer 16

Rare
Usually affects individuals who are heterozygous
Very occasionally affected homozygotes may be born to 2 affected heterozygote parents
But homozygotes maybe more severe phenotype and an earlier age of onset
Both sexes equally likely to transmit and inherit the disorder
Affected individuals have a 50% chance of of having offspring with the disease

Question 17

Describe Achondroplasia

eg fgfr

Answer 17

Disproportionate small stature.
short arms and legs, a large head, and characteristic facial features
ACH is caused by a heterozygous mutation in the fibroblast growth factor receptor 3-gene on chromosome 4p16.3
characteristic clinical and radiographic findings usually sufficient
If diagnostic uncertainty, molecular genetic testing to detect a mutation in FGFR3.
Detects mutations in 99% of affected individuals.
Autosomal dominant.
80% of individuals with achondroplasia have parents with average stature and have achondroplasia as the result of a de novo gene mutation.

Question 18

An individual with achondroplasia who has a reproductive partner with average stature has a what% risk in each pregnancy of having a child with achondroplasia

Answer 18

50

Question 19

When both parents have achondroplasia:
what% risk of having offspring with average stature
what% risk of having achondroplasia,
what% risk of having homozygous achondroplasia (a lethal condition)

Answer 19

25
50
25

Question 20

What is Familial hypercholesterolemia (FHC)

Answer 20

Autosomal dominant
Levation of serum cholesterol bound to low density lipoprotein (LDL),
Promotes deposition of cholesterol in the skin, tendons, and coronary arteries
2 clinical forms (heterozygous and homozygous)
Homozygous :
More severe clinically -earlier presentation, usually in the first 2 decades of life
The aortic root is prone to develop atherosclerotic plaque at an early age
he ranges of serum cholesterol and LDL-cholesterol (mg per dl), are:
250-450 and 200-400 in heterozygotes,
>500 and >450 in homozygous

Question 21

Describe autosomal recessive

Answer 21

Affected person can be of either sex
Usually born to unaffected heterozygote parents (both carriers)
e.g. Sickle Cell disease, cystic fibrosis. Affected individuals carry 2 mutant alleles, one from each parent

Question 22

Describe cystic fibrosis

Answer 22

Autosomal recessive
Buildup of thick, sticky mucus
Progressive damage to the respiratory system and chronic digestive system problems.
Mucus clogs the airways, leading to severe breathing problems and bacterial infections in the lungs, causing chronic coughing, wheezing, and inflammation.
Mucus buildup and infections cause permanent lung damage, including the formation of scar tissue (fibrosis) and cysts in the lungs.
Mucus buildup in the pancreas reduces the production of insulin leading to diabetes and prevents digestive enzymes from reaching the intestines leading to malnutrition.
Improved treatments

Question 23

Describe X-linked recessive ie who is affected

Answer 23

Affected individuals usually male and born to unaffected parents, inheriting the mutation from their mother
No father to son transmission of mutation

Question 24

Describe X-linked dominant ie who is affected

Answer 24

Affected individuals either male or female, but more females affected
Usually one parent is affected
No father to son transmission of mutation

Question 25

What is locus heterogeneity?

Answer 25

Occurs when mutations at multiple genomic loci are capable of producing the same phenotype, and each individual mutation is sufficient to cause the specific phenotype independently
a defect in any of these genes may result in a similar clinical outcome
This means that parents apparently carrying the same recessive disorder may not have affected offspring

Question 26

Give examples of what locus heterogeneity can cause

Answer 26

Autosomal recessive deafness
Retinitis pigmentosa (retinal disease with rod and cone degeneration
Usher syndrome (autosomal recessive forms)

Question 27

Describe Locus Heterogeneity: Bardet-Biedl

Answer 27

Night blindness, tunnel vision, learning disabilities, kidney disease,extra toes/fingers, obesity, gonad abnormalities
Caused in mutations in any of at least 15 genes
All regulate cilia function

Question 28

What is penetrance?

Answer 28

Of a single gene disorder is the probability that a person with the mutant allele will express the disease phenotype
Dominant conditions – show in heterozygotes, therefore by definition, show 100% penetrance
Non penetrance – due to other effects (epigenetic, other genes, environmental) modifying the expression of the phenotype
Age-related penetrance means that the disease phenotype does not show until later in life
Due to accumulation of harmful products, gradual process of cell death