Lecture 15 - Actin Mutations Flashcards
Define the 6 Different Actin Isoforms, including where they are expressed?
- a-Actin - ACTC1 (Cardiac), ACTA1 (Skeletal), ACTA2 (SM - Vasculature)
- B-Actin - ACTB (Widely expressed)
- y-Actin - ACTG1 (Widely expressed), ACTG2 (SM - GI, Prostate, Bladder)
How Similar in sequence are different isoforms of Actin?
Display 90% Sequence Homology
Are Observed Actin Mutations Generally Heterozygous or Homozgous?
Heterozygous, as Homozygous mutations produce non-viable cells (unless redundancy occurs)
(i) What Mutations occur in ACTA1?
(ii) What diseases are associated with them (Give Example)?
(i) >200, majority of which are single aa substitutions
(ii) Produce Skeletal Muscle diseases
* e.g., Nemaline Myopathy - thread-like actin aggregates accumulate in the cytoplasm/nucleus
(i) What Mutations occur in ACTA2?
(ii) What diseases are associated with them (Give Example)?
(i) 80+ Mutations, 90% of which are missense mutations
(ii) Expressed in Vasculature, hence leads to defects in regulation of blood flow pressure
* e.g., Hereditary Thoracic Aortic Aneurysm - weakening/ swelling of aorta
(i)What specific mutations have been associated with Thoracic Aortic Aneurysm?
(ii) How do they affect actin structure/dynamics?
- Mutations in residues 118 and 353 are associated with disease progression
- Form a binding pocket in SDI of one actin monomer where SDII of another monomer docks during actin polymerisation (mutations prevent correct filament formation)
(i) What Mutations occur in ACTC1?
(ii) What diseases are associated with them (Give Example)?
(i) Over 70 Mutations, 90% of which are missense mutations
(ii) Expressed in Cardiac tissue, hence diseases manifest as heart disease
* e.g., Hypertrophic Cardiomyopathy - abnormally thick heart muscle
(i) What Mutations occur in ACTB?
(ii) How do different types of mutation impact the disease that is produced?
(i) >70 Mutations, 50% of which are missense mutations
(ii):
* Missense mutations - associated with wide range of defects characterised by Baraitser-Winter Syndrome
* Non-Missense mutations - lead to haploinsufficiency and disease not-associated with Baraitser Winter Syndrome
How do Missense mutations of ACTB Impact Actin Cytoskeleton Structure/Dynamics?
Patients display similar expression levels to normal patients, however mutations prevent depolymerisation (identified using polymerisation inhibitor)
How do Non-Missense ACTB Mutations Impact Patient Health/Physiology?
Patients displayed much lower levels of Fibroblast and Lymphoblastic cell lines, as well as deficiencies in several key cell cycle control factors
(i) What Mutations occur in ACTG1?
(ii) What diseases are associated with them (Give Example)?
(i) 50 mutations, all (except one) of which are missense mutations
(ii):
* >50% of mutations cause deafness (may play role in the contraction of sensory epithelia of ear)
* Some mutations are also associated with Baraitser-Winter Syndrome (Phenocopies ACTB Mutations)
What diseases are associated with mutations in ACTG2?
Megasystis Microcolon-Intestinal Hypoperistalsis Syndrome (failue of SM to contract in Colon/Small Intestine)
- How do Individuals Acquire Actin Mutations?
- Do they always cause disease?
- Often Heriditary in Nature, Affecting the entire organism (expressed in relevant tissues)
- Not always as:
* Redundancy may occur with some actin isoforms (dependent on expression)
* Mutations are often heterozygous, therefore the other allele may compensate
What can looking at the number of mutations observed in different regions of actin tell you?
Indicates which regions of the actin monomer are critical for its function, with decreased number of observed mutations suggesting any mutations are not survivable
How does the toxin of V. Cholerae exert a toxic effect on cells via actin?
V. Cholorae produces an actin-crosslinking domain (ACD) toxin, which cross-links actin together into high order oligomers, sequestering to prevent it carrying out its normal function
