HUMAN M UTATION
M UTATION IN BRIEF
HUMAN MUTATION Mutation in Brief 31: E1544-E1550 (2010) Online
Received 31 Decem ber 2009; accepted revised m anuscript 12 April 2010.
© 2010 WILEY-LISS, INC.
Recessive Mutations in RYR1 Are a Common Cause
of Congenital Fiber Type Disproportion
Nigel F. Clarke1,2, Leigh B. Waddell1,2, Sandra T. Cooper1,2, Margaret Perry2,3, Robert L.L. Sm ith4,
Andrew J. Kornberg5, Francesco Muntoni6, Suzanne Lillis7, Volker Straub8, Kate Bushby8, Michela Guglieri8, Mary
D. King9, Michael A. Farrell10, Isabelle Marty11, Joel Lunardi11, Nicole Monnier11, and Kathryn N. North1,2
1Institute for Neuroscience and Muscle Research, Children’s Hospital at Westm ead, Sydney, Australia; 2Discipline of
Paediatrics and Child Health, University of Sydney, Sydney, Australia; 3Anaesthetic Departm ent, The Children’s Hospital at
Westm ead, Sydney, Australia; 4John Hunter Children’s Hospital and University Discipline of Paediatrics and Child Health,
Newcastle, Australia; 5Departm ent of Neurology, Royal Children’s Hospital, Melbourne, Australia; 6Dubowitz Neurom uscular
Centre, Institute of Child Health, London, UK; 7Diagnostic Genetics Laboratory, Guy’s Hospital, London, UK; 8Institute of
Hum an Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK; 9Neurology
Departm ent, Children’s University Hospital Tem ple St, Dublin, Ireland; 10Departm ent of Neuropathology, Beaum ont Hospital,
Dublin, Ireland. 11Biochim ie et Génétique Moléculaire, CHU Grenoble / INSERM U836, Grenoble, France
* Correspondence to Dr. Nigel Clarke, Children’s Hospital at Westm ead, Locked Bag 4001, WESTMEAD, NSW 2145,
Australia. Telephone: +61 2 98451453. Fax: +61 2 9845 3389. E-m ail: NigelC@chw.edu.au.
Com m unicated by Ravi Savarirayan
ABSTRACT: The main histological abnormality in congenital fiber type disproportion (CFTD) is
hypotrophy of type 1 (slow twitch) fibers compared to type 2 (fast twitch) fibers. To investigate
whether mutations in RYR1 are a cause of CFTD we sequenced RYR1 in seven CFTD families in
whom the other known causes of CFTD had been excluded. We identified compound
heterozygous changes in the RYR1 gene in four families (five patients), consistent with autosomal
recessive inheritance. Three out of five patients had ophthalmoplegia, which may be the most
specific clinical indication of mutations in RYR1. Type 1 fibers were at least 50% smaller, on
average, than type 2 fibers in all biopsies. Recessive mutations in RYR1 are a relatively common
cause of CFTD and can be associated with extreme fiber size disproportion. ©2010 Wiley-Liss, Inc.
KEY WORDS: RYR1, congenital myopathy, congenital fiber type disproportion, multi-minicore disease
Congenital fiber type disproportion is a form of congenital myopathy in which consistent type 1 fiber
hypotrophy relative to type 2 fibers is the main histological abnormality [Clarke and North, 2003]. Of the four
genetic causes that have been reported to date, TPM3 (MIM# 191030) appears a common cause compared to
ACTA1 (MIM# 102610) , TPM2 (MIM# 190990) and SEPN1 (MIM# 606210) [Laing et al., 2004; Clarke et al.,
E1550 Clarke et al.
Brandis A, Aronica E, Goebel HH. 2008. TPM2 mutation. Neuromuscul Disord. 18:1005.
Clarke NF, North KN. 2003. Congenital fiber type disproportion--30 years on. J Neuropathol Exp Neurol. 62:977-989.
Clarke NF, Kidson W, Quijano-Roy S, Estournet B, Ferreiro A, Guicheney P, Manson JI, Kornberg AJ, Shield LK, North
KN. 2006. SEPN1: Associated with congenital fiber-type disproportion and insulin resistance. Ann Neurol. 59:546-552.
Clarke NF, Ilkovski B, Cooper S, Valova VA, Robinson PJ, Nonaka I, Feng JJ, Marston S, North K. 2007. The pathogenesis
of ACTA1-related congenital fiber type disproportion. Ann Neurol. 61:552-561
Clarke NF, Kolski H, Dye DE, Lim E, Smith RLL, Patel R, Fahey MC, Bellance R, Romero N, Johnson ES, Labarre-Vila A,
Monnier N, Laing NG, North KN. 2008. Mutations in TPM3 are a common cause of congenital fiber type disproportion.
Ann Neurol. 63:329-337.
Cooper ST, Kizana E, Yates JD, Lo HP, Yang N, Wu ZH, Alexander IE, North KN. 2007. Dystrophinopathy carrier
determination and detection of protein deficiencies in muscular dystrophy using lentiviral MyoD-forced myogenesis.
Neuromuscul Disord. 17:276-284.
Cooper ST, Lo HP, North KN. 2003. Single section Western blot: improving the molecular diagnosis of the muscular
dystrophies. Neurology. 61:93-97.
Jungbluth H, Davis MR, Muller C, Counsell S, Allsop J, Chattopadhyay A, Messina S, Mercuri E, Laing NG, Sewry CA,
Bydder G, Muntoni F. 2004. Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1
mutations. Neuromuscul Disord. 14:785-790.
Jungbluth H, Muller CR, Halliger-Keller B, Brockington M, Brown SC, Feng L, Chattopadhyay A, Mercuri E, Manzur AY,
Ferreiro A, Laing NG, Davis MR, Roper HP, Dubowitz V, Bydder G, Sewry CA, Muntoni F. 2002. Autosomal recessive
inheritance of RYR1 mutations in a congenital myopathy with cores. Neurology. 59:284-287.
Jungbluth H, Zhou H, Hartley L, Halliger-Keller B, Messina S, Longman C, Brockington M, Robb SA, Straub V, Voit T,
Swash M, Ferreiro A, Bydder G, Sewry CA, Muller C, Muntoni F. 2005. Minicore myopathy with ophthalmoplegia
caused by mutations in the ryanodine receptor type 1 gene. Neurology. 65:1930-1935.
Laing NG, Clarke NF, Dye DE, Liyanage K, Walker KR, Kobayashi Y, Shimakawa S, Hagiwara T, Ouvrier R, Sparrow JC,
Nishino I, North KN, Nonaka I. 2004. Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol.
Lawlor MW, Dechene ET, Roumm E, Geggel AS, Moghadaszadeh B, Beggs AH. 2009. Mutations of tropomyosin 3 (TPM3)
are common and associated with type 1 myofiber hypotrophy in congenital fiber type disproportion. Hum Mutat. 31:176-
Monnier N, Marty I, Faure J, Castiglioni C, Desnuelle C, Sacconi S, Estournet B, Ferreiro A, Romero N, Laquerriere A,
Lazaro L, Martin JJ, Morava E, Rossi A, van der KA, de Visser M, Verschuuren C, Lunardi J. 2008. Null mutations
causing depletion of the type 1 ryanodine receptor (RYR1) are commonly associated with recessive structural congenital
myopathies with cores. Hum Mutat. 29:670-678.
Monnier N, Romero NB, Lerale J, Landrieu P, Nivoche Y, Fardeau M, Lunardi J. 2001. Familial and sporadic forms of
central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor.
Hum Mol Genet. 10:2581-2592.
Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P. 2006. Mutations in RYR1 in malignant hyperthermia and central
core disease. Hum Mutat. 27:977-989.
Zhou H, Brockington M, Jungbluth H, Monk D, Stanier P, Sewry CA, Moore GE, Muntoni F. 2006. Epigenetic allele
silencing unveils recessive RYR1 mutations in core myopathies. Am J Hum Genet. 79:859-868.