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Flashcards in Mutational Mechanisms and Disease Deck (31)

What are the four major mechanisms whereby genetic mutations lead to disease:

1) loss of function of the protein (most common)
2) gain of function of the protein
3) acquisition of a novel property by the mutant protein
4) perturbed expression of a gene at the wrong time (heterochronic expression) or in the wrong place (ectopic expression), or both.


What are five examples of loss of protein function we have talked about this unit?

Turner syndrome, Duchenne Muscular Dystrophy, HNPP (Hereditary Neuropathy with Pressure Palsies), Osteogenesis Imperfecta Type 1, Alpha-thalassemia


Duchenne Muscular Dystrophy genetic/biochemical basis. What is the inheritance?

DMD Xp21.2. Deletion, TOTAL loss of function.
[Large deletions of multiple exons, nonsens mutations, frameshift mutations] X-linked inheritance


What is Becker Muscular Dystrophy? What distinguishes this from Duchenne's?

Milder form of DMD, partial loss of function.


Clinical manifestation of Duchenne's?

•Boys with abnormal gait at 3-5 years
•Calf pseudohypertrophy
•Gower maneuver (YouTube)
•Progressive involvement of respiratory muscles
•Median age of death 18 years
•Women may ! cardiomyopathy


What EXACTLY does HNPP stand for?

Hereditary Neuropathy with Liability to Pressure Palsies


What is HNPP and what is its cause?

due to DELETION of PMP22 gene leading to a phenotype where patients have temporary (usually reversible) neuropathy when pressure is applied to various nerves. Just as your arm may go to sleep if left in a certain position, these patients are more sensitive to pressure on nerves and their limbs can ‘go to sleep’ for longer periods of time (hours, days, to months)


Osteogenesis imperfecta type I:

Nonsense (stop) mutations / frameshift mutations in COL1A1 results in premature termination. Reduced amount of normal COL1A1 (collagen) protein causing a ‘milder’ form of osteogenesis imperfect. Clinically characterized by increased fractures, brittle bones, and blue sclera. Normal production of COL1A2 (ratio COL1A1/COL1A2 is 2:1, 2 copies of both genes normally present).


4 Gain-of-Function Mutations we have talked about?

1) Hemoglobin Kempsey
2) Achondroplasia
3) Alzheimer disease in Trisomy 21
4) Charcot-Marie-Tooth


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. Polycythemia (overproduction of RBC to compensate).



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.



due to DUPLICATION of PMP22 gene (HNPP is due to deletion of same)


3 novel protein functions we have discussed?

Sickle cell anemia, Huntington disease, Osteogenesis imperfecta types (2, 3, 4--all more serious that type I)


Sickle cell anemia

the Glu6Val mutation of the beta globin gene results in a hemoglobin molecule which transports oxygen essentially normally.
However under low oxygen states the Val residue leads to polymerization of hemoglobin into long protein-fibers which deform and restrict the normally flexible red blood cells


Huntington disease:

A triplet repeat disorder where by expansion of CAG repeat ‘triplets’ in the gene increase the number of glutamine residues (the CAG codon codes for glutamine). Increased polyglutamine residues above a certain threshold leads to a novel toxic effect on the huntingtin protein


2 examples of Ectopic or Heterochronic Expression Mutations (altered expression)

Cancer, hereditary persistence of fetal hemoglobin


8 steps at which mutations can disrupt normal protein formation:

1. Transcription 2. Translation 3. Polypeptide folding 4. Post-transcriptional modification 5. Assembly of monomers into a holomeric protein 6. Subcellular localization of the polypeptide or the holomer 7. Cofactor or prosthetic group binding to the polypeptide 8. Function of a correctly folded, assembled, and localized protein produced in normal amounts


Error in Step 1, transcription (2 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


Error in Step 2 translation (1)

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


Error in Step 3 Polypeptide folding

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


Error in Step 4. Post-transcriptional modification

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.


Error in step 5. Assembly of monomers into a holomeric protein

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


Error in Step 6 Subcellular localization of the polypeptide or the holomer

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


Error in Step 7 Cofactor or prosthetic group binding to the polypeptide

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


Error in Step 8 Function of a correctly folded, assembled, and localized protein produced in normal amounts

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


Fragile X Syndrome is caused by?

CGG repeats in 5'UTR which silence translation. Lack of functional protein. (>200 repeats)


Fragile X Tremor/Ataxia Syndrome (FXTAS) caused by?

60-200 CGG repeats in 5'UTR. 2-5 fold increase in FMR1 mRNA lead to neuronal intranuclear inclusions


Friedreich ataxia caused by?

GAA repeats in intron, impaired transcriptional elongation, loss of frataxin function. Increased Fe in mitochondria, reduced heme synthesis, reduced activity of Fe-S complex containing proteins.


Huntington disease caused by?

CAG repeats in exon confer novel properties on protein, protein overinteracts with cofactors causing loss of fxn? Expansion is PATERNALLY INHERITED THANK YOU


Myontonic dystrophy caused by?

Expanded CUG repeats bind increased amounts of mRNA binding proteins, cause impaired RNA splicing. Expansion is MATERNALLY INHERITED YAH WELCOME