Reference: Bryan KE, et al. (2006) Effects of human deafness gamma-actin mutations (DFNA20/26) on actin function. J Biol Chem 281(29):20129-39

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Abstract

Six point mutations in non-muscle gamma-actin at the DFNA20/26 locus cause autosomal-dominant non-syndromic hearing loss. The molecular basis for the hearing loss is unknown. We have engineered each gamma-actin mutation into yeast actin to investigate the effects of these mutations on actin function in vivo and in vitro. Cells expressing each of the mutant actins as the sole actin in the cell were viable. Four of the six mutant strains exhibit significant growth deficiencies in complete media and an inability to grow on glycerol as a sole carbon source implying a mitochondrial defect(s). These four strains exhibit abnormal mitochondrial morphology although the mitochondrial DNA is retained. All of the mutant cells exhibit an abnormally high percentage of fragmented/non-polarized actin cables or randomly distributed actin patches. Five of the six mutants display strain-specific vacuole morphological abnormalities. Two of the purified mutant actins exhibit decreased thermal stability and increased rates of nucleotide exchange, indicative of increased protein flexibility. V370A actin alone polymerizes abnormally. It aggregates in low ionic strength buffer and polymerizes faster than WT actin, probably in part because of enhanced nucleation. Mixtures of WT and V370A actins display kinetic properties in proportion to the mole fraction of each actin in the mixture. No dominant effect of the mutant actin was observed. Our results suggest that a major factor in the deafness caused by these mutations is an altered ability for the actin filaments to be properly regulated by actin-binding proteins rather than an inability to polymerize.

Reference Type
Journal Article
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Bryan KE, Wen KK, Zhu M, Rendtorff ND, Feldkamp M, Tranebjaerg L, Friderici KH, Rubenstein PA
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