SU2.3

Question 1

What is the definition of a loss-of-function (LOF) mutation?

Answer 1

A mutation that reduces or completely eliminates the activity of a gene product.

Question 2

If one functional copy of a gene produces sufficient protein for a normal phenotype, a loss-of-function mutation in the other copy will have a _____ inheritance pattern.

Answer 2

recessive

Question 3

If a loss-of-function mutation results in a dominant inheritance pattern, what are the two likely mechanisms?

Answer 3

Haploinsufficiency or a dominant-negative effect.

Question 4

What is haploinsufficiency?

Answer 4

A situation where a single functional copy of a dosage-sensitive gene is insufficient to produce a normal phenotype.

Question 5

Familial hypercholesterolemia (FH) is an example of which type of dominant loss-of-function mechanism?

Answer 5

Haploinsufficiency.

Question 6

Loss-of-function mutations in which gene cause Familial Hypercholesterolemia (FH)?

Answer 6

The LDLR gene.

Question 7

What is the physiological consequence of reduced LDL receptor activity in Familial Hypercholesterolemia?

Answer 7

The accumulation of LDL (low-density lipoprotein) in the bloodstream.

Question 8

What is a dominant-negative effect?

Answer 8

A mechanism where the mutated gene product actively interferes with the function of the normal gene product.

Question 9

Type II Osteogenesis Imperfecta (brittle bone disease) is an example of which genetic mechanism?

Answer 9

A dominant-negative effect.

Question 10

What is the definition of a gain-of-function (GOF) mutation?

Answer 10

A mutation where the gene product acquires a new or enhanced function, or is expressed at an inappropriate time or location.

Question 11

What is the usual inheritance pattern for gain-of-function mutations?

Answer 11

Dominant or dominant-negative.

Question 12

The activation of oncogenes in cancers is an example of what type of mutation?

Answer 12

A gain-of-function mutation.

Question 13

Dynamic mutation disorders, such as those involving triplet repeat expansions, are examples of what type of mutation?

Answer 13

A gain-of-function mutation.

Question 14

What is the term for the phenomenon where a single disease phenotype can be caused by a variety of different genetic mutations?

Answer 14

Genetic heterogeneity.

Question 15

What is allelic heterogeneity?

Answer 15

When different mutations within the same gene cause the same or similar disease phenotypes.

Question 16

What is locus heterogeneity?

Answer 16

When mutations in different genes lead to the same or a similar phenotype.

Question 17

Different mutations in the _____ gene are a classic example of allelic heterogeneity, leading to four distinct disorders.

Answer 17

RET

Question 18

What type of mutation in the RET gene leads to Multiple Endocrine Neoplasia type 2A (MEN2A)?

Answer 18

Gain-of-function missense mutations, for example at codon 634.

Question 19

What specific mutation in the RET gene causes the more aggressive Multiple Endocrine Neoplasia type 2B (MEN2B)?

Answer 19

The M918T mutation in exon 16, which results in a strong gain of function.

Question 20

What is the functional effect of the various missense mutations in the RET gene that cause Familial Medullary Thyroid Carcinoma (FMTC)?

Answer 20

A gain of function, though it results in a less aggressive phenotype than MEN2A/B.

Question 21

What type of mutation in the RET gene causes Hirschsprung Disease (HSCR)?

Answer 21

Loss-of-function mutations, such as nonsense, frameshift, or splice site mutations.

Question 22

What is the clinical outcome of loss-of-function mutations in the RET gene that cause Hirschsprung Disease?

Answer 22

Absence of enteric ganglia (aganglionosis), which leads to bowel obstruction.

Question 23

Sensorineural hearing loss (SNHL), caused by mutations in approximately 150 different genes, is a key example of which genetic principle?

Answer 23

Locus heterogeneity.

Question 24

What is the most common form of inheritance for sensorineural hearing loss (SNHL)?

Answer 24

Autosomal recessive.

Question 25

How can two parents, both affected with autosomal recessive hearing loss, have children with normal hearing?

Answer 25

Locus heterogeneity; the parents' deafness is caused by mutations in two different genes, so their children are heterozygous carriers at both loci.

Question 26

Mutations in the GJB2 gene, causing non-syndromic SNHL, affect the function of which protein?

Answer 26

Connexin 26, which is involved in forming gap junctions in the cochlea.

Question 27

Mutations in the MYO7A gene are associated with Usher syndrome type 1B. What is the function of the Myosin VIIA protein?

Answer 27

It is important for hair cell structure in the inner ear.

Question 28

Mutations in the OTOF gene cause non-syndromic SNHL by affecting otoferlin. What process is otoferlin involved in?

Answer 28

Synaptic transmission in the cochlea.

Question 29

Pendred syndrome, which involves deafness and goiter, is caused by mutations in which gene?

Answer 29

The SLC26A4 gene.

Question 30

What is the function of Pendrin, the protein encoded by the SLC26A4 gene?

Answer 30

It is involved in anion transport.

Question 31

What is the definition of a modifier gene?

Answer 31

A gene that influences the expression of another gene, thereby suppressing, enhancing, or modifying the severity or onset of a disease.

Question 32

In the context of modifier genes, what is the term for the mutation that is the principal cause of the disease phenotype?

Answer 32

The primary mutation.

Question 33

What group of autosomal recessive disorders, caused by reduced haemoglobin production, has varied clinical outcomes due to modifier genes?

Answer 33

Thalassemia.

Question 34

The severity of thalassemia depends on maintaining a critical balance between which two protein chains?

Answer 34

The α-globin and β-globin chains.

Question 35

What is the primary cause of β-thalassemia?

Answer 35

Mutations in the HBB gene, which encodes the β-globin chain.

Question 36

How does the co-inheritance of α-thalassemia act as a modifier to lessen the severity of β-thalassemia?

Answer 36

It reduces the production of α-globin chains, which helps to reduce the imbalance between the α- and β-globin chains.

Question 37

Smoking is an environmental factor that can increase the risk of rheumatoid arthritis in people with which specific genetic predisposition?

Answer 37

Certain HLA genotypes.

Question 38

What is Phenylketonuria (PKU)?

Answer 38

An autosomal recessive disorder caused by mutations in the PAH gene, leading to elevated phenylalanine levels.

Question 39

Untreated Phenylketonuria (PKU) can lead to what severe neurological problems?

Answer 39

Intellectual disability, seizures, and other neurological problems.

Question 40

What environmental intervention, if started in infancy, can alleviate the severe phenotypes of Phenylketonuria (PKU)?

Answer 40

A diet low in phenylalanine (Phe).

Question 41

In addition to a specialised diet, what supplementation can support neurological health in individuals with PKU?

Answer 41

Tyrosine supplementation.