title: RYR1 mutations are a common cause of congenital myopathies with central nuclei.
abstract: OBJECTIVE
  Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM.
  
  
  METHODS
  We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations.
  
  
  RESULTS
  The high incidence in South African patients (n = 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings.
  
  
  CONCLUSIONS
  Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies.
authors.affiliation: Department of Paediatric Neurology, School of Child and Adolescent Health, University of Cape Town, Red Cross Children's Hospital, Cape Town, South Africa.
authors.forename: J M
authors.initials: JM
authors.lastname: Wilmshurst
authors.forename: S
authors.initials: S
authors.lastname: Lillis
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: K
authors.initials: K
authors.lastname: Pillay
authors.forename: H
authors.initials: H
authors.lastname: Henderson
authors.forename: W
authors.initials: W
authors.lastname: Kress
authors.forename: C R
authors.initials: CR
authors.lastname: Müller
authors.forename: A
authors.initials: A
authors.lastname: Ndondo
authors.forename: V
authors.initials: V
authors.lastname: Cloke
authors.forename: T
authors.initials: T
authors.lastname: Cullup
authors.forename: E
authors.initials: E
authors.lastname: Bertini
authors.forename: C
authors.initials: C
authors.lastname: Boennemann
authors.forename: V
authors.initials: V
authors.lastname: Straub
authors.forename: R
authors.initials: R
authors.lastname: Quinlivan
authors.forename: J J
authors.initials: JJ
authors.lastname: Dowling
authors.forename: S
authors.initials: S
authors.lastname: Al-Sarraj
authors.forename: S
authors.initials: S
authors.lastname: Treves
authors.forename: S
authors.initials: S
authors.lastname: Abbs
authors.forename: A Y
authors.initials: AY
authors.lastname: Manzur
authors.forename: C A
authors.initials: CA
authors.lastname: Sewry
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005060:Europe; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology*; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism; D013019:South Africa
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel