title: Variable myopathic presentation in a single family with novel skeletal RYR1 mutation.
abstract: We describe an autosomal recessive heterogeneous congenital myopathy in a large consanguineous family. The disease is characterized by variable severity, progressive course in 3 of 4 patients, myopathic face without ophthalmoplegia and proximal muscle weakness. Absence of cores was noted in all patients. Genome wide linkage analysis revealed a single locus on chromosome 19q13 with Zmax = 3.86 at θ = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Direct sequencing of the main candidate gene within the candidate region, RYR1, was performed. A novel homozygous A to G nucleotide substitution (p.Y3016C) within exon 60 of the RYR1 gene was found in patients. ARMS PCR was used to screen for the mutation in all available family members and in an additional 150 healthy individuals. This procedure confirmed sequence analysis and did not reveal the A to G mutation (p.Y3016C) in 300 chromosomes from healthy individuals. Functional analysis on EBV immortalized cell lines showed no effect of the mutation on RyR1 pharmacological activation or the content of intracellular Ca(2+) stores. Western blot analysis demonstrated a significant reduction of the RyR1 protein in the patient's muscle concomitant with a reduction of the DHPRα1.1 protein. This novel mutation resulting in RyR1 protein decrease causes heterogeneous clinical presentation, including slow progression course and absence of centrally localized cores on muscle biopsy. We suggest that RYR1 related myopathy should be considered in a wide variety of clinical and pathological presentation in childhood myopathies.
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ruben
authors.initials: R
authors.lastname: Attali
authors.forename: Sharon
authors.initials: S
authors.lastname: Aharoni
authors.forename: Susan
authors.initials: S
authors.lastname: Treves
authors.forename: Ori
authors.initials: O
authors.lastname: Rokach
authors.forename: Michal
authors.initials: M
authors.lastname: Becker Cohen
authors.forename: Yakov
authors.initials: Y
authors.lastname: Fellig
authors.forename: Rachel
authors.initials: R
authors.lastname: Straussberg
authors.forename: Talya
authors.initials: T
authors.lastname: Dor
authors.forename: Muhannad
authors.initials: M
authors.lastname: Daana
authors.forename: Stella
authors.initials: S
authors.lastname: Mitrani-Rosenbaum
authors.forename: Yoram
authors.initials: Y
authors.lastname: Nevo
mesh_terms: D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D055815:Young Adult
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium
references.citation: Hum Mutat. 2010 Jul;31(7):E1544-50
references.pmid: 20583297
references.citation: Biochem J. 1994 Aug 1;301 ( Pt 3):661-5
references.pmid: 8053891
references.citation: J Biol Chem. 1994 Apr 1;269(13):9413-5
references.pmid: 7511586
references.citation: Hum Mol Genet. 2006 Sep 15;15(18):2791-803
references.pmid: 16940308
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4164-9
references.pmid: 10097181
references.citation: Curr Opin Pharmacol. 2008 Jun;8(3):319-26
references.pmid: 18313359
references.citation: Nature. 1988 Jan 28;331(6154):315-9
references.pmid: 2448641
references.citation: J Biol Chem. 2001 Dec 21;276(51):48077-82
references.pmid: 11673462
references.citation: Trends Mol Med. 2012 Nov;18(11):644-57
references.pmid: 23069638
references.citation: Biophys J. 2004 Nov;87(5):3193-204
references.pmid: 15347586
references.citation: Neuromuscul Disord. 2005 Oct;15(9-10):577-87
references.pmid: 16084090
references.citation: Hum Mutat. 2012 Jun;33(6):981-8
references.pmid: 22473935
references.citation: Neuromuscul Disord. 2002 Dec;12(10):930-8
references.pmid: 12467748
references.citation: Hum Mol Genet. 2003 Feb 15;12(4):379-88
references.pmid: 12566385
references.citation: Hum Mutat. 2008 May;29(5):670-8
references.pmid: 18253926
references.citation: J Cell Biol. 1984 Nov;99(5):1735-42
references.pmid: 6386826
references.citation: Hum Mol Genet. 2003 May 15;12(10):1171-8
references.pmid: 12719381
references.citation: Biochemistry. 1994 Aug 9;33(31):9078-84
references.pmid: 8049209
references.citation: J Biol Chem. 1998 May 29;273(22):13403-6
references.pmid: 9593671
references.citation: Neuromuscul Disord. 2008 Jun;18(6):433-42
references.pmid: 18482838
references.citation: Semin Pediatr Neurol. 2011 Dec;18(4):216-20
references.pmid: 22172416
references.citation: Genomics. 1996 May 15;34(1):24-41
references.pmid: 8661021
references.citation: Neurology. 2008 Jan 8;70(2):114-22
references.pmid: 17538032
references.citation: Arch Dis Child. 2003 Dec;88(12):1051-5
references.pmid: 14670767
references.citation: J Biol Chem. 1999 Feb 26;274(9):5995-6002
references.pmid: 10026226
references.citation: Hum Mol Genet. 2001 Dec 1;10(25):2879-87
references.pmid: 11741831
references.citation: Ann Neurol. 2010 Nov;68(5):717-26
references.pmid: 20839240
references.citation: Hum Mutat. 2006 Oct;27(10):977-89
references.pmid: 16917943
references.citation: Nat Genet. 2002 Jan;30(1):97-101
references.pmid: 11731797
references.citation: Brain. 2007 Aug;130(Pt 8):2024-36
references.pmid: 17483490
references.citation: Acta Neuropathol. 2012 Oct;124(4):575-81
references.pmid: 22752422
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20108-13
references.pmid: 18077436
references.citation: Hum Genet. 1986 Aug;73(4):320-6
references.pmid: 3017841
references.citation: Bioinformatics. 2005 May 1;21(9):2123-5
references.pmid: 15647291
references.citation: Muscle Nerve. 2006 Jun;33(6):715-31
references.pmid: 16477617