Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy

TLDR

Cypher is a member of a newly identified family of proteins that contain an N‑terminal PDZ domain and one to three C‑terminal LIM domains. In vitro studies show that Cypher’s individual domains independently localize to the Z‑line through interactions with α‑actinin or other Z‑line components. Cypher knockout mice develop a severe congenital myopathy, die postnatally from multi‑muscle failure, and the data reveal that Cypher is essential for maintaining the Z‑line during contraction, functioning as a linker‑strut rather than being required for sarcomere assembly.

Abstract

Cypher is a member of a recently emerging family of proteins containing a PDZ domain at their NH2 terminus and one or three LIM domains at their COOH terminus. Cypher knockout mice display a severe form of congenital myopathy and die postnatally from functional failure in multiple striated muscles. Examination of striated muscle from the mutants revealed that Cypher is not required for sarcomerogenesis or Z-line assembly, but rather is required for maintenance of the Z-line during muscle function. In vitro studies demonstrated that individual domains within Cypher localize independently to the Z-line via interactions with α-actinin or other Z-line components. These results suggest that Cypher functions as a linker-strut to maintain cytoskeletal structure during contraction.