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We have identified a patient affected by a relatively severe form of central core disease (CCD), carrying a heterozygous deletion (amino acids 4863–4869) in the pore-forming region of the sarcoplasmic reticulum calcium release channel. The functional effect of this deletion was investigated (i) in lymphoblastoid cells from the affected patient and her mother, who was also found to harbour the mutation and (ii) in HEK293 cells expressing recombinant mutant channels. Lymphoblastoid cells carrying the RYR1 deletion exhibit an ‘unprompted’ calcium release from intracellular stores, resulting in significantly smaller thapsigargin-sensitive intracellular Ca 2+  stores, compared with lymphoblastoid cells from control individuals. Blocking the RYR1 with dantrolene restored the intracellular calcium stores to levels similar to those found in control cells. Single channel and [ 3 H]ryanodine binding measurements of heterologously expressed mutant channels revealed a reduced ion conductance and loss of ryanodine binding and regulation by Ca 2+ . Heterologous expression of recombinant RYR1 peptides and analysis of their membrane topology demonstrate that the deleted amino acids are localized in the lumenal loop connecting membrane-spanning segments M8 and M10. We provide evidence that a deletion in the lumenal loop of RYR1alters channel function and causes CCD.

Clinical and functional effects of a deletion in a COOH-terminal lumenal loop of the skeletal muscle ryanodine receptor