Mutational Mechanisms and Disease Flashcards
Loss-of-function Mutation
In general, many metabolic diseases (enzyme defect in a metabolic pathway) are due to loss of function mutations and these loss-of-function mutations are often (but not exclusively) inherited as autosomal recessive diseases as both alleles need to be damaged before the phenotype develops.
Loss-of-function mutations are 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.
What are some examples of diseases caused by loss of function mutations?
-Duchenne Muscular dystrophy is characterized by *complete loss of protein.
-Alpha-thalassemia is characterized by REDUCTION in amount of protein by deletion of an alpha-thalassemia gene.
-Turner syndrome is characterized by loss of an entire chromosome.
Hereditary neuropathy with liability to pressure palsies (HNPP) due to deletion of PMP22 gene.
-Osteogenesis imperfecta type I
Gain-of-Function mutations
Gain-of-function mutations caused by point mutations (missense mutations) often (but not always) show autosomal dominant inheritance patterns as carrying one mutant allele is sufficient to cause disease
Often 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).
What are some examples of diseases mediated by this?
Hemoglobin Kempsey (Beta hemoglobin gene, Asp99Asn missense mutation): leads to a hemoglobin molecule which has higher than normal oxygen affinity, and is less able to unload oxygen in the tissues.
Achondroplasia: FGFR3 Gly380Arg mutation increases the normal signaling though intracellular tyrosine kinase domain (essentially having the receptor constitutively in the ‘turned-on’ state).
Alzheimer disease in Trisomy 21): Patients with an extra copy of chromosome 21 have 3 total copies of the APP (21q21) leading to increased production of APP protein which contributes to early-onset Alzheimer disease in this patient population.
Charcot-Marie-Tooth disease type 1: due to duplication of PMP22 gene (see HNPP above) which leads to elevated PMP22 protein.
Novel property mutations
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).
What are some diseases?
-Sickle cell anemia
-Huntington’s disease
Ectopic or heterochronic Expression Mutation
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.
Sample Diseases:
-Cancers
Hereditary persistence of fetal hemoglobin: the normal switch from fetal to adult hemoglobin does not occur and fetal hemoglobin, which has a higher affinity for oxygen, remains expressed beyond infancy. One mechanism for this is deletion of several genes in the beta hemoglobin locus, but retention of the fetal (γ) gene such that the γ-globin gene continues to be expressed because the β-globin gene is missing and the normal switch from γ to β cannot occur.
Steps at which mutations can Disrupt the normal protein
Transcription
Diseases related: ________
Thalassemias and Hereditary persistent of fetal hemoblogin
Steps at which mutations can Disrupt the normal protein
Translation
Diseases related: ________
Thalassemias
Steps at which mutations can Disrupt the normal protein
Polypeptide Folding (3)
Diseases related: ________
Hemoglobinopathies (Hb Hammersmith)
Steps at which mutations can Disrupt the normal protein
Post-translational modification (4)
Diseases related: ________
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.
Steps at which mutations can Disrupt the normal protein
Assembly of monomers into a holomeric protein (5)
Diseases related: ________
Osteogenesis imperfecta
Steps at which mutations can Disrupt the normal protein
Subcellular localization of the polypeptide or the holomer(6)
Diseases related: ________
Familial hypercholesterolemia
Steps at which mutations can Disrupt the normal protein
Cofactor binding (7)
Diseases related: ________
Types of homocystinuria due to poor or absent binding of the cofactor (pyridoxal phosphate) to the cystathionine synthase apoenzyme
