Mutational Mechanisms and Disease

Question 1

Loss-of-Function Mutations: Mechanisms

Answer 1

Caused by genetic mutations (deletions, insertions, or rearrangements) that eliminate (or reduce) the function of the protein. Of the four major mechanisms, this is the most common genetic mechanism leading to human genetic disease

Question 2

Loss-of-Function Mutations: examples of diseases

Answer 2

• Duchenne Muscular dystrophy
• alpha-thalassemia
• Turner syndrome
• hereditary retinoblastoma
• hereditary neuropathy with liability to pressure palsies
• osteogenesis imperfect type I

Question 3

Gain-of-Function Mutations: Mechanisms

Answer 3

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

Question 4

Gain-of-Function Mutations: examples of diseases

Answer 4

• Hemoglobin kempsey
• Achondroplasia
• Alxhemier disease
• Charcot-Marie-Tooth

Question 5

Novel Property Mutations: (relatively uncommon) Mechanisms

Answer 5

Caused by genetic mutations (often missense) that confer a novel property on the protein, without necessarily altering its normal functions. Although the introduction of a novel property has sometimes been advantageous from an evolutionary standpoint, the majority of such changes result in a novel protein property that reduces fitness (i.e. can lead to disease).

Question 6

Novel Property Mutations: examples of disease

Answer 6

Sickle cell anemia and Huntington disease

Question 7

Ectopic or Heterochronic Expression Mutations: (relatively uncommon; seen in cancers) Mechanisms

Answer 7

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

Question 8

Ectopic or Heterochronic Expression Mutations: examples of diseases

Answer 8

• Cancers

- Hereditary persistence of fetal hemoglobin

Question 9

Step: Transcription

Disease examples:

Answer 9

Thalassemias due to reduced or absent production of a globin mRNA because of deletions or mutations in regulatory or splice sites of a globin gene Hereditary persistence of fetal hemoglobin, which results from increased postnatal transcription of one or more γ-globin genes

Question 10

Step: Translation

Disease examples:

Answer 10

Thalassemias due to nonfunctional or rapidly degraded mRNAs with nonsense or frameshift mutations

Question 11

Step: Polypeptide folding

Disease examples:

Answer 11

More than 70 hemoglobinopathies are due to abnormal hemoglobins with amino acid substitutions or deletions that lead to unstable globins that are prematurely degraded, e.g., Hb Hammersmith

Question 12

Step: Post-translational modification

Disease examples:

Answer 12

I-cell disease, a lysosomal storage disease that is due to a failure to add a phosphate group to mannose residues of lysosomal enzymes. The mannose 6- phosphate residues are required to target the enzymes to lysosomes.

Question 13

Step: Assembly of monomers into a holomeric protein

Disease examples:

Answer 13

Types of osteogenesis imperfecta in which an amino acid substitution in a procollagen chain impairs the assembly of a normal collagen triple helix

Question 14

Step: Subcellular localization of the polypeptide or the holomer
Disease examples:

Answer 14

Familial hypercholesterolemia mutations (class 4), in the carboxyl terminus of the LDL receptor, that impair the localization of the receptor to clathrin- coated pits, preventing the internalization of the receptor and its subsequent recycling to the cell surface

Question 15

Step: Cofactor or prosthetic group binding to the polypeptide
Disease examples:

Answer 15

Types of homocystinuria due to poor or absent binding of the cofactor (pyridoxal phosphate) to the cystathionine synthase apoenzyme

Question 16

Step: Function of a correctly folded, assembled, and localized protein produced in normal amounts
Disease examples:

Answer 16

Diseases in which the mutant protein is normal in nearly every way, except that one of its critical biological activities is altered by an amino acid substitution; e.g., in Hb Kempsey, impaired subunit interaction locks hemoglobin into its high oxygen affinity state

Question 17

‘unstable repeat expansion’ disorders

Answer 17

These genes contain tri, or tetra-nucleotide repeats which are believed to make the genes susceptible to slipped mispairing during DNA replication. The consequence of this is that the repeat numbers for each allele are prone to change from parent to offspring. An expansion of repeat numbers beyond certain thresholds can lead to clinical disease

Question 18

In Huntington disease, alleles with >40 CAG repeats inevitably lead to clinical disease and a general correlation is found between repeat number and disease severity (i.e. the larger the repeat number, the greater the clinical severity in terms of age-of-onset and progression)

Answer 18

> 40 CAG repeats
repeat number and disease severity (i.e. the larger the repeat number, the greater the clinical severity in terms of age-of-onset and progression)

Question 19

Genetic anticipation

Answer 19

the expansion of repeats from parent to offspring, leads to more severe disease in the offspring generation

Question 20

Expansion of noncoding repeats and loss of function

Consequences and examples:

Answer 20

Consequences: 
-impaired transcription 
-mutant RNA not made
-mutant protein not made
Ex: 
-Fragile X
-Friedreich ataxia

Question 21

Expansion of noncoding repeats conferring novel properties

Consequences and examples:

Answer 21

Consequences: 
-RNA has novel property (abnormal RNA binds and soaks up RNA-binding proteins --> affects other gene products) 
-Mutant RNA is made 
-Mutant protein not made
Ex.
-Myotonic dystrophy types 1 and 2
-FXTAS

Question 22

Expansion of codons in exons

Consequences and examples:

Answer 22

Consequences: 
-novel property on expressed protein
-Mutant RNA is made and protein is made and is toxic
Ex: 
-Huntington disease
-Spinocerebellar ataxias