Acta Neuropathologica

, Volume 124, Issue 4, pp 575–581 | Cite as

Samaritan myopathy, an ultimately benign congenital myopathy, is caused by a RYR1 mutation

  • Johann Böhm
  • Esther Leshinsky-Silver
  • Stéphane Vassilopoulos
  • Stéphanie Le Gras
  • Tally Lerman-Sagie
  • Mira Ginzberg
  • Bernard Jost
  • Dorit Lev
  • Jocelyn Laporte
Original Paper

Abstract

Congenital myopathies describe a group of inherited muscle disorders with neonatal or infantile onset typically associated with muscle weakness, respiratory involvement and delayed motor milestones. We previously reported a novel congenital myopathy in an inbred Samaritan family. All patients displayed severe neonatal hypotonia and respiratory distress, and unlike other congenital myopathies, a constantly improving health status. As clinical and pathological data did not point to preferential candidate genes, we performed exome sequencing complemented by linkage analysis to identify the mutation causing the benign Samaritan congenital myopathy. We identified the homozygous p.Tyr1088Cys mutation in RYR1, encoding the skeletal muscle ryanodine receptor. This sarcoplasmic reticulum calcium channel is a key regulator of excitation–contraction coupling (ECC). Western blot and immunohistofluorescence revealed a significant decrease of the RYR1 protein level and an abnormal organization of skeletal muscle triad markers as caveolin-3, dysferlin and amphiphysin 2. RYR1 mutations are associated with different myopathies and malignant hyperthermia susceptibility. The index patient had mild hyperthermia following anesthesia, indicating that the inbred Samaritan population might be a risk group for this disorder. Our results suggest an aberrant ECC as the primary cause of this disease, and broaden the clinical consequences of RYR1 defects.

Keywords

Congenital myopathy Samaritan RYR1 Exome sequencing Malignant hyperthermia 

Supplementary material

401_2012_1007_MOESM1_ESM.doc (76 kb)
Supplementary material 1 (DOC 77 kb)
401_2012_1007_MOESM2_ESM.tif (7.5 mb)
Supplementary material 2 (TIFF 7703 kb)

References

  1. 1.
    Bevilacqua JA, Monnier N, Bitoun M, Eymard B, Ferreiro A, Monges S, Lubieniecki F, Taratuto AL, Laquerriere A, Claeys KG, Marty I, Fardeau M, Guicheney P, Lunardi J, Romero NB (2011) Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. Neuropathol Appl Neurobiol 37:271–284PubMedCrossRefGoogle Scholar
  2. 2.
    Bonne-Tamir B, Korostishevsky M, Redd AJ, Pel-Or Y, Kaplan ME, Hammer MF (2003) Maternal and paternal lineages of the Samaritan isolate: mutation rates and time to most recent common male ancestor. Ann Hum Genet 67:153–164PubMedCrossRefGoogle Scholar
  3. 3.
    Clarke NF, Waddell LB, Cooper ST, Perry M, Smith RL, Kornberg AJ, Muntoni F, Lillis S, Straub V, Bushby K, Guglieri M, King MD, Farrell MA, Marty I, Lunardi J, Monnier N, North KN (2010) Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion. Hum Mutat 31:E1544–E1550PubMedCrossRefGoogle Scholar
  4. 4.
    Gillard EF, Otsu K, Fujii J, Khanna VK, de Leon S, Derdemezi J, Britt BA, Duff CL, Worton RG, MacLennan DH (1991) A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics 11:751–755PubMedCrossRefGoogle Scholar
  5. 5.
    Jungbluth H, Wallgren-Pettersson C, Laporte J (2008) Centronuclear (myotubular) myopathy. Orphanet J Rare Dis 3:26PubMedCrossRefGoogle Scholar
  6. 6.
    Lev D, Sadeh M, Watemberg N, Dabby R, Vinkler C, Ginzberg M, Lerman-Sagie T (2006) A benign congenital myopathy in an inbred Samaritan family. Eur J Paediatr Neurol 10:182–185PubMedCrossRefGoogle Scholar
  7. 7.
    Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760PubMedCrossRefGoogle Scholar
  8. 8.
    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25:2078–2079PubMedCrossRefGoogle Scholar
  9. 9.
    Liewluck T (2007) A benign congenital myopathy in an inbred Samaritan family. Eur J Paediatr Neurol 11:55 (author reply 55–56)PubMedCrossRefGoogle Scholar
  10. 10.
    Monnier N, Ferreiro A, Marty I, Labarre-Vila A, Mezin P, Lunardi J (2003) A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. Hum Mol Genet 12:1171–1178PubMedCrossRefGoogle Scholar
  11. 11.
    North K (2008) What’s new in congenital myopathies? Neuromuscul Disord 18:433–442PubMedCrossRefGoogle Scholar
  12. 12.
    Phillips MS, Fujii J, Khanna VK, DeLeon S, Yokobata K, de Jong PJ, MacLennan DH (1996) The structural organization of the human skeletal muscle ryanodine receptor (RYR1) gene. Genomics 34:24–41PubMedCrossRefGoogle Scholar
  13. 13.
    Quane KA, Healy JM, Keating KE, Manning BM, Couch FJ, Palmucci LM, Doriguzzi C, Fagerlund TH, Berg K, Ording H et al (1993) Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet 5:51–55PubMedCrossRefGoogle Scholar
  14. 14.
    Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P (2006) Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat 27:977–989PubMedCrossRefGoogle Scholar
  15. 15.
    Romero NB, Monnier N, Viollet L, Cortey A, Chevallay M, Leroy JP, Lunardi J, Fardeau M (2003) Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia. Brain 126:2341–2349PubMedCrossRefGoogle Scholar
  16. 16.
    Sato K, Pollock N, Stowell KM (2010) Functional studies of RYR1 mutations in the skeletal muscle ryanodine receptor using human RYR1 complementary DNA. Anesthesiology 112:1350–1354PubMedCrossRefGoogle Scholar
  17. 17.
    Schreuder LT, Nijhuis-van der Sanden MW, de Hair A, Peters G, Wortmann S, Bok LA, Morava E (2010) Successful use of albuterol in a patient with central core disease and mitochondrial dysfunction. J Inherit Metab Dis. doi:10.1007/s10545-010-9085-7 PubMedGoogle Scholar
  18. 18.
    Sewry CA (2008) Pathological defects in congenital myopathies. J Muscle Res Cell Motil 29:231–238PubMedCrossRefGoogle Scholar
  19. 19.
    Takeshima H, Nishimura S, Matsumoto T, Ishida H, Kangawa K, Minamino N, Matsuo H, Ueda M, Hanaoka M, Hirose T et al (1989) Primary structure and expression from complementary DNA of skeletal muscle ryanodine receptor. Nature 339:439–445PubMedCrossRefGoogle Scholar
  20. 20.
    Wilmshurst JM, Lillis S, Zhou H, Pillay K, Henderson H, Kress W, Muller CR, Ndondo A, Cloke V, Cullup T, Bertini E, Boennemann C, Straub V, Quinlivan R, Dowling JJ, Al-Sarraj S, Treves S, Abbs S, Manzur AY, Sewry CA, Muntoni F, Jungbluth H (2010) RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann Neurol 68:717–726PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang KM, Hu P, Wang SW, Feher JJ, Wright LD, Wechsler AS, Spratt JA, Briggs FN (1996) Salbutamol changes the molecular and mechanical properties of canine skeletal muscle. J Physiol 496(Pt 1):211–220PubMedGoogle Scholar
  22. 22.
    Zhang Y, Chen HS, Khanna VK, De Leon S, Phillips MS, Schappert K, Britt BA, Browell AK, MacLennan DH (1993) A mutation in the human ryanodine receptor gene associated with central core disease. Nat Genet 5:46–50PubMedCrossRefGoogle Scholar
  23. 23.
    Zhou H, Jungbluth H, Sewry CA, Feng L, Bertini E, Bushby K, Straub V, Roper H, Rose MR, Brockington M, Kinali M, Manzur A, Robb S, Appleton R, Messina S, D’Amico A, Quinlivan R, Swash M, Muller CR, Brown S, Treves S, Muntoni F (2007) Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies. Brain 130:2024–2036PubMedCrossRefGoogle Scholar
  24. 24.
    Zorzato F, Fujii J, Otsu K, Phillips M, Green NM, Lai FA, Meissner G, MacLennan DH (1990) Molecular cloning of cDNA encoding human and rabbit forms of the Ca2+ release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum. J Biol Chem 265:2244–2256PubMedGoogle Scholar

Web resources

  1. Exome Variant Server, NHLBI Exome Sequencing Project (ESP), Seattle, WA (URL: http://evs.gs.washington.edu/EVS/)
  2. Online Mendelian Inheritance in Man (OMIM), http://www.omim.org/

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Johann Böhm
    • 1
    • 2
    • 3
    • 4
    • 5
  • Esther Leshinsky-Silver
    • 6
    • 7
    • 8
  • Stéphane Vassilopoulos
    • 9
  • Stéphanie Le Gras
    • 10
  • Tally Lerman-Sagie
    • 7
    • 8
  • Mira Ginzberg
    • 7
  • Bernard Jost
    • 10
  • Dorit Lev
    • 7
    • 8
    • 11
  • Jocelyn Laporte
    • 1
    • 2
    • 3
    • 4
    • 5
  1. 1.Department of Translational Medecine and NeurogeneticsIGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire)IllkirchFrance
  2. 2.InsermIllkirchFrance
  3. 3.CNRSIllkirchFrance
  4. 4.Université de StrasbourgIllkirchFrance
  5. 5.Chaire de Génétique HumaineCollège de FranceIllkirchFrance
  6. 6.Molecular Genetics LaboratoryWolfson Medical CenterHolonIsrael
  7. 7.Metabolic Neurogenetic ClinicWolfson Medical CenterHolonIsrael
  8. 8.Sackler School of MedicineTel-Aviv UniversityTel-AvivIsrael
  9. 9.Université Pierre et Marie Curie, University Paris 06, UM76, Institut de Myologie, INSERM U974 and CNRS UMR7215ParisFrance
  10. 10.DNA Microarrays and Sequencing PlatformIGBMCIllkirchFrance
  11. 11.Institute of Medical GeneticsWolfson Medical CenterHolonIsrael

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