Principles of genetic disorders

Question 1

What are the four types of genetic disorders?

Answer 1

1. Frame shift
2. Point mutation
3. Trinucleotide-repeat mutations
4. Mutations within noncoding sequences

Question 2

What are the three types of point mutations?

Answer 2

Substitution:
ex) THE FAT CAT ATE THE RAT; THE FAT HAT ATE THE RAT

Insertion:
ex) THE FAT CAT ATE THE RAT; THE FAT HCA TAT ETH ERA T

Deletion:
ex) THE FAT CAT ATE THE RAT; THE FAT ATA TET HER AT
(The C is missing)

Question 3

Substitutions can be:

Answer 3

1) Transitions: interchanges of purines (A,G) or of pyrimidines (C,T)
-Involves bases of similar shape (both one ring or two ring)

2) Transversions: interchanges of purines for pyrimidine bases
-Involves exchange of one ring and two ring structures

Question 4

Insertions or deletions can lead to what?

Answer 4

Frameshift mutations: All of the triplets are off by one (frame-shifting indels)

Often results in total loss of function of the protein:
-“O” blood type results from a frameshift mutation and loss of function of the red blood cell antigen
- Tay-Sachs disease

Question 5

What happens if a multiple of three nucleotides is inserted or deleted:

Answer 5

The reading frame is preserved: non-frameshifting indels
ex) cystic fibrosis mutation

Question 6

What type of deletion is this?

Answer 6

One nucleotide deletion: frameshift
-protein is no longer functional

Question 7

What type of deletion is this?

Answer 7

Three nucleotide deletion: non-frameshift, but loss of amino acid
ex) cystic fibrosis

Question 8

What type of point mutation has little or no change of funtion?

Answer 8

Silent or conservative missense

Question 9

What type of point mutation has significant change in function?

Answer 9

nonconservative missense
ex) sickle cell anemia

Question 10

Describe a non-sense point mutation:

Answer 10

Nucleotide triplet being changed becomes a stop codon, then there is a premature ending of translation-> truncated (shortened) protein.

Question 11

What type of point mutation is this?

Answer 11

Non-conservative missense
-sickle-cell anemia

Question 12

What type of point mutation is this?

Answer 12

Nonsense
-beta-thalassemia

Question 13

Some people can’t be infected with the HIV virus because of mutations, what type of receptor does HIV use, and what type of mutation happens to protect an individual form HIV?

Answer 13

HIV uses chemokine receptor, CCR5, to enter cells; a deletion in the CCR5 gene thus protects from HIV infection

Question 14

What does the Sickle-cell trait protect against?

Answer 14

Malaria:
RBC’s that have some sickle-cell hemoglobin are not good hosts for the parasite that causes sickle-cell disease: thus the trait (heterozygote patient) is protective.

However, the homozygote (all hemoglobin is sickle-cell hemoglobin) is more vulnerable to the disease than the rest of the population

Question 15

What are the types of genetic disorders?

Answer 15

Mendelian disorders:

        Autosomal mutations: -Dominant: structural proteins (Marfan's syndrome-structural protein deficit)

-Recessive: Enzyme defects (Lysosomal storage diseases)

             X-Linked disorders: -Hemophilia

Question 16

Due to mutations in single genes that have large effects:

Answer 16

-Thought that everyone has 5-8 non-beneficial gene mutations (Most of these have relatively small effects on phenotype)

-80-85% familial, rest are new mutations:
This can differ depending on the type of disorder: 80% of those with achondroplasia (defect in elongation of the bone growth plate) are new mutations

-Traits can be dominant, recessive, or codominant

Question 17

-Manifested in heterozygous or homozygous state

-Usually have at least one parent with the disorder:
Exception: spontaneous mutation occurs
New mutations: more common when father is older

-Usually manifests in each generation

Answer 17

Autosomal dominant disorders

Question 18

How likely the mutated gene is to be expressed:

Answer 18

Penetrance (autosomal dominant disorder)

explained: If something is autosomal dominant but has 50% penetrance, a heterozygote may only have a 50% chance of showing the disease phenotype.

Question 19

How “much” the disorder-causing gene is expressed:

Answer 19

Expressivity (autosomal dominant disorder)

-All heterozygotes still show the trait
-The intensity of the trait differs from person to person

Question 20

True or False: Most mutations lead to a protein that has reduced function or is produced less (loss of function mutation)

Answer 20

True

Question 21

What to autosomal dominant disorders tend to involve?

Answer 21

Genes that are part of metabolic pathways or regulation of these pathways

-some involve defects in structural proteins

Question 22

Disorders due to insufficient production of an enzyme tend to be recessive. Why?

Answer 22

This pattern of inheritance helps explain why some genetic disorders related to enzyme deficiencies are more commonly observed in individuals who have inherited two mutated alleles, which is a recessive trait. The carriers (heterozygous individuals) can pass on the mutated allele in the population without displaying the disorder themselves.

Question 23

Gain of function mutations are ______, but can be ____________________.

Answer 23

rare; autosomal dominant

Question 24

Autosomal dominant disorders:

Answer 24

study!

Question 25

Disorder of connective tissues, manifested principally by changes in the skeleton, eyes, and cardiovascular system

Epidemiology: prevalence of 1 in 5000

Etiology: Disorder due to a defect in gene for fibrillin-1
-75-85% are familial; the rest are new mutations
-Autosomal dominant: chromosome 15, 600 distinct mutations-most are missense

Pathophysiology: Fibrillin is an important component of elastic connective tissue, provides a “scaffold” for elastic fiber deposition

-Loss of fibrillin-1 explains many findings:
ex) aneurysm formation, ligamentous laxity, defects in eye structure

-others are more difficult to explain
-Thought that increased skeletal growth is due to increased bioavailability of TGF-beta, which is affected by fibrillin levels( TGF-beta can also impact smooth muscle development)

Answer 25

Marfan Syndrome

Question 26

What are the clinical findings and prognosis of Marfan syndrome?

Answer 26

Clinical findings:
-Tall, with very long extremeties and lax ligaments
-Dislocation of the lens
-Cardiovascular changes; Mitral valve prolapse-malformed and “weak” heart valve
-Weakness in the muscular layers of the aorta, which can lead to aortic valvular incompetence and development of serious aneurysms

-Variability expressivity; Some individuals may lack certain clinical findings. ex) skeletal findings with no ocular findings

Prognosis: Variable, main causes of mortality and morbidity are aneurysms and valvular defects.
-Surgical repair of aneurysms, heart valves

Question 27

-Largest category of Mendelian disorders
-Basic rules of Mendelian inheritance apply

As well:
-The expression of the defect tends to be more uniform than is autosomal dominant dosorders

-complete penetrance is common

-Onset is frequently early in life

-Although new mutations associated with recessive disorders do occur, they are rarely detected clinically, since the individual with a new mutation is an asymptomatic heterozygote

-Many of the mutated genes encode enzymes
In heterozygotes, equal amounts of normal and defective enzyme are synthesized.
Usually that natural “margin of safety” ensures that cells with half the usual complement of the enzyme function normaly.

Answer 27

Autosomal recessive disorders

Question 28

Consequences of enzyme defects:

Answer 28

Accumulation of a substrate:
-Sometimes the substrate can be toxic in high concentrations

Blockage of a metabolic pathway

Failure to inactivate another enzyme or substrate:
ex) alpha-1 anti-trypsin deficiency

Question 29

Can be from a range of problems with lysosomal enzymes:
-Lack of the enzyme, leading up to build-up of a substrate within a cell that is toxic.
-Misfolding of the lysosomal enzyme
-Lack of protein “activator” that binds to the substrate and improves the ability of the enzyme to act on it.

Answer 29

Lysosomal Storage diseases

Question 30

Pathophysiology of lysosomal diseases:

Answer 30

-In the example shown, a complex substrate is normally degraded by a series of lysosomal enzymes (A,B, and C) into soluble end products

-Deficiency or malfunction of one of the enzymes (ex B) -> incomplete catabolism-> insoluble intermediates that accumulate in the lysosomes-> “primary storage” problem
-Huge, numerous lysosomes interfere
with cellular function
-Second storage Problem= toxic effects from defective autophagy.

Question 31

What is autophagy?

Answer 31

“cellular housecleaning”

Question 32

Most common lysosomal storage disease
-Between 1 in 20,000 and 1 in 40,000 live
births.
-Autosomal recessive inheritance
Defect in the gene for glucocerebrosidase
-Enzyme cleaves the glucose residues from
ceramide, found in cell membranes.
-Glucosylceramide accumulates in
lysosomes.
Metabolites accumulate mainly within macrophages and other phagocytic cells as the phagocytose dying cells and metabolize the membranes.
-This can lead to the activation or loss of
function of the phagocytes.

Answer 32

Gaucher Disease

Question 33

Gaucher Disease Type I:

Answer 33

Involves organs outside the central nervous system-99% of cases
-Findings are mostly within the spleen and
bone.
-Enlargement of the spleen and
liver.
-Weakened bones->frequent
fractures

Question 34

Gaucher disease Type II:

Answer 34

Involves the CNS as well as other organs
-Hepatosplenomegaly and rapid neurological
deterioration, with death in early childhood.
-CNS macrophage activation->production of
toxic signals by macrophages-> neuronal
death.

Question 35

All sex-linked disorders are ___________, and the vast majority are ____________.

Answer 35

x-linked; recessive

Question 36

Males with mutations affecting the y-linked genes are usually ___________, and hence there is no y-linked inheritance.

Answer 36

infertile

Question 37

Features of x-linked disorders:

Answer 37

An affected male does not transmit the disorder to his sons, but all daughters are carriers.
-Sons of heterozygous women have a 1 in 2
chance of receiving the mutant gene.
The heterozygous female usually does not express the full phenotypic change because of the paired normal allele.

Question 38

Gene carried on the x chromosomes and usually only manifests in males:

Answer 38

A male with a mutant allele on his single x chromosome = hemizygous for the allele

Question 39

x-linked recessive inheritance:

Answer 39

-Transmitted by healthy heterozygous female carriers to affected males

-Affected males to their obligate carrier daughters.
-consequent risk to male grandchildren
through these daughters.
-Affected males can’t transmit to sons.

Question 40

Hemophilia A:

Answer 40

Loss of function of a coagulation factor necessary for clotting.
-Affects over 20,000 men in North America
-Different mutations confer different
bleeding risk-thousands of mutations have
been identified with variable impacts on
coagulation.

Clinical features:
-Bruising and prolonged bleeding with minimal trauma.
-Mucosal bleeding, hematomas in joint spaces (hemarthrosis)

Question 41

The person being “examined” (usually the one with the genetic condition) is known as the__________

Answer 41

proband

Question 42

Diagram developed around the proband is called:

Answer 42

Pedigree

Question 43

Frequent appearance of the disease throughout generations:

Answer 43

Autosomal dominant pedigree

May not show a typical 50% chance of transmission (remember reduced penetrance)

Affects both males and females

Question 44

Autosomal recessive pedigree

Answer 44

The risk of autosomal recessive disorders manifesting increases if there is consanguinity.
-If a homozygote has offspring with a
heterozygote, can also look deceptively
frequent.
Often parents of affected proband not affected.

Question 45

Only males appear affected.

Trait is never passed from father to son

May see “knight’s move” pattern of transmission.

Answer 45

X-linked recessive pedigree