Mutational Mechanisms and Disease Flashcards
Loss-of-Function Mutations: Mechanisms
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
Loss-of-Function Mutations: examples of diseases
- Duchenne Muscular dystrophy
- alpha-thalassemia
- Turner syndrome
- hereditary retinoblastoma
- hereditary neuropathy with liability to pressure palsies
- osteogenesis imperfect type I
Gain-of-Function Mutations: Mechanisms
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)
Gain-of-Function Mutations: examples of diseases
- Hemoglobin kempsey
- Achondroplasia
- Alxhemier disease
- Charcot-Marie-Tooth
Novel Property Mutations: (relatively uncommon) Mechanisms
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).
Novel Property Mutations: examples of disease
Sickle cell anemia and Huntington disease
Ectopic or Heterochronic Expression Mutations: (relatively uncommon; seen in cancers) Mechanisms
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.
Ectopic or Heterochronic Expression Mutations: examples of diseases
- Cancers
- Hereditary persistence of fetal hemoglobin
Step: Transcription
Disease examples:
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
Step: Translation
Disease examples:
Thalassemias due to nonfunctional or rapidly degraded mRNAs with nonsense or frameshift mutations
Step: Polypeptide folding
Disease examples:
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
Step: Post-translational modification
Disease examples:
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.
Step: Assembly of monomers into a holomeric protein
Disease examples:
Types of osteogenesis imperfecta in which an amino acid substitution in a procollagen chain impairs the assembly of a normal collagen triple helix
Step: Subcellular localization of the polypeptide or the holomer
Disease examples:
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
Step: Cofactor or prosthetic group binding to the polypeptide
Disease examples:
Types of homocystinuria due to poor or absent binding of the cofactor (pyridoxal phosphate) to the cystathionine synthase apoenzyme
Step: Function of a correctly folded, assembled, and localized protein produced in normal amounts
Disease examples:
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
‘unstable repeat expansion’ disorders
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
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)
> 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)
Genetic anticipation
the expansion of repeats from parent to offspring, leads to more severe disease in the offspring generation
Expansion of noncoding repeats and loss of function
Consequences and examples:
Consequences: -impaired transcription -mutant RNA not made -mutant protein not made Ex: -Fragile X -Friedreich ataxia
Expansion of noncoding repeats conferring novel properties
Consequences and examples:
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
Expansion of codons in exons
Consequences and examples:
Consequences: -novel property on expressed protein -Mutant RNA is made and protein is made and is toxic Ex: -Huntington disease -Spinocerebellar ataxias
