Mutational Mechanisms of Disease

Question 1

Loss of function

Answer 1

Caused by genetic mutations (deletions, insertions, or rearrangements) that eliminate (or reduce) the function of the protein.
MOST COMMON genetic mechanism.

Often have mutations in the coding region and an abnormal protein. Ex: beta thalassemia.

Question 2

Examples of loss of function?

Answer 2

Duchenne’s (complete loss of a protein).
Alpha-thalassemia (deleted copy)
Turner syndrome: lose entire chromosome
Hereditary Rb: 2nd hit leading to loss of tumor suppressor
Hereditary neuropathy, pressure palsies: deletion of a gene
Osteogenesis imperfecta type I: stop/frameshift mutations, premature termination. Reduced amount of collagen. Milder form.

MANY metabolic diseases. OFTEN inherited as AR

Question 3

Gain of function

Answer 3

Genetic mutations (often missense, sometimes promoter) that enhance one or more normal functions of a protein (increased expression, increased half-life, decreased degradation, increased activity).

Question 4

Gain of fx. examples

Answer 4

Hb-Kempsey: bind O2 tighter, unloading harder
Achondroplasia: increased normal signaling through intracellular tyrosine kinase domain (receptor is ‘constitutively on’)
Charcot-Marie-Tooth: type 1A. duplication of gene (vs HNPP), elevated PMP22 protein.

OFTEN AD inheritance (carrying one mutant allele sufficient for disease).

Question 5

Novel Property Mutations

Answer 5

Relatively uncommon.
Caused by mutations (often missense) that confer a novel property on the protein, without necessarily altering its normal fx. Soemtimes advantageous, but mostly bad.

Question 6

Novel property examples:

Answer 6

Sickle cell: Low oxygen states valine leads to polymerization into fibers
Huntingtons: expansion of CAG, increased glut above a certain threshold leads to novel toxic effect

Question 7

Ectopic or Heterochronic Expression Mutations

Answer 7

Caused by mutations that alter regulatory regions of a gene and alter the timing (heterchronic= wrong time) or location (ectopic) of expression.

Question 8

Examples of ectopic/heterochronic expression

Answer 8

Cancer: gene that is normally silent (in differentiated cells for example) is abnormally expressed (turned back on) leads to abnormal proliferation. Oncogenes are example.

HPFH: normal switch from fetal to adult Hb does not happen, fetal Hb has higher affinity for O2. Delete genes in beta locus but retain the fetal gamma gene, so it keeps being expressed.

Question 9

What are repeat sequences subject to?

Answer 9

Slipped mispairing. So repeat #’s change in passage to offspring.

Question 10

Genetic anticipation

Answer 10

disease severity worsening with subsequent generations.

Question 11

Expansion of noncoding repeats (get loss of function)

Answer 11

Fragile X, Friedreich ataxia

Question 12

Expansion of noncoding repeats (get novel properties)

Answer 12

Myotonic dystrophy types 1 and 2

Fragile X associated tremor/ataxia (FXTAS)

Question 13

Expansion of codons in exons

Answer 13

Huntingtons

Spinocerebellar ataxia