10/17 ARMC4 Mutations Flashcards
ARMC4 Mutations Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry
What is Primary Ciliary Dyskinesia (PCD) ?
a disease whose symptoms include chronic respiratory disease and situs inversus left/right (L/R) asymmetry defects in ~50% of affected individuals
What are Outer dynein arms (ODAs)
large multiprotein complexes that drive ciliary motility that comprise of comprise of light, intermediate and heavy chain proteins such as DNAH5 and DNAI1
What is the association between ODAs and PCD?
ODA defects have been previously implicated in PCD indicating ODAs and therefore ciliary motility play a key role in PCD symptom development and L/R asymmetry
What genes are commonly mutated in PCD patients?
ARMC4 premature termination mutants leading to ARMC4 deficiency causes PCD and L/R asymmetry randomization as evidenced by their presence in 12 PCD individuals from 10 families
Does ARMC4 have a conserved role in establishing L/R asymmetry?
Armc4 defects cause dosage dependent randomization of heart looping, confirming armc4 plays a role in establishing L/R asymmetry in zebrafish
Can ARMC4 WT mRNA rescue morpholino (MO) -based suppression of armc4 in zebrafish?
Co-injection of human ARMC4 WT mRNA and MO armc4 does significantly rescue the phenotype
What are the phenotypic effects of Armc4 mutation in mice?
○ Armc4 mutation in mice causes abnormal laterality, cardiovascular anomalies, immotile/slowed dyskinetic motile respiratory cilia, reduction of ODAs, all consistent with the PCD phenotype
Where is ARMC4 localized in human motile respiratory cilia?
ARMC4 is localized to the respiratory ciliary axonemes (a ciliary ‘skeletal’ component)
What is the functional consequence of ARMC4 defects?
ARMC4 mutants experience reduced to no ciliary motility
How do Armc4 mutations affect outer dynein arm (ODA) composure?
ARMC4 deficiency causes a reduction but not complete loss of ODA assembly, and affects ODAs along the whole axoneme evidenced by ODA abnormalities in all cross sections analyzed
What molecular defects are caused by ARMC4 deficiency?
ARMC4 deficiency causes there to be no distal axoneme presence of the ODA components of heavy chain DNAH5 and intermediate chain DNA12 as well as mislocalization of the ODA component DNAH9, a previously unreported ODA defect pattern
What is the role of ARMC4 in ciliary assembly?
ARMC4 has no structural role in ODA assembly, but functions in their targeting and docking
What did the paper, ARMC4 Mutations Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry, conclude?
AMC4 is a ciliary protein required for axonemal docking and targeting of ODAs, which in turn are required for ciliary motility driving proper L/R asymmetry, two characteristics of primary cell dyskinesia.
