The mutant mice express a knockin (KI) amino acid mutation Ile4895Thr (IT) in the skeletal muscle type 1 ryanodine receptor /Ca2+ release channel (RyR1). The IT mutation corresponds to the human I4898T RyR1 mutation, which causes a severe form of central core disease (CCD) in heterozygous carriers. RyR1 plays a key role in excitation-contraction (EC) coupling in skeletal muscle by releasing Ca2+ from the sarcoplasmic reticulum (SR) and triggering muscle contraction. Mutations in RYR1 have been associated with central core disease (CCD), multiminicore disease, nemaline rod myopathy, and malignant hyperthermia.
The IT mutation affects a highly conserved GGIG4899 motif in the selectivity filter of the Ca2+ release channel. The mutation disrupts Ca2+ release channel conductance without altering the integrity of the RyR1 protein complex. The homozygous IT/IT mice are born paralyzed in all skeletal muscles, are unable to breathe and die perinatally. IT/IT embryos show a generalized developmental delay including growth retardation, marked delay in ossification, myogenesis, dermatogenesis, and cardiovascular development. Heterozygous IT/+ mice are viable and fertile. They exhibit a slowly progressive congenital myopathy with spatiotemporal development of minicores, cores, and rods in their skeletal muscle.
