title: Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy.
abstract: OBJECTIVE
  To identify causative genes for centronuclear myopathies (CNM), a heterogeneous group of rare inherited muscle disorders that often present in infancy or early life with weakness and hypotonia, using next-generation sequencing of whole exomes and genomes.
  
  
  METHODS
  Whole-exome or -genome sequencing was performed in a cohort of 29 unrelated patients with clinicopathologic diagnoses of CNM or related myopathy depleted for cases with mutations of MTM1, DNM2, and BIN1. Immunofluorescence analyses on muscle biopsies, splicing assays, and gel electrophoresis of patient muscle proteins were performed to determine the molecular consequences of mutations of interest.
  
  
  RESULTS
  Autosomal recessive compound heterozygous truncating mutations of the titin gene, TTN, were identified in 5 individuals. Biochemical analyses demonstrated increased titin degradation and truncated titin proteins in patient muscles, establishing the impact of the mutations.
  
  
  CONCLUSIONS
  Our study identifies truncating TTN mutations as a cause of congenital myopathy that is reported as CNM. Unlike the classic CNM genes that are all involved in excitation-contraction coupling at the triad, TTN encodes the giant sarcomeric protein titin, which forms a myofibrillar backbone for the components of the contractile machinery. This study expands the phenotypic spectrum associated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes.
authors: From the Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research (O.C.-B., P.B.A., K.S.-A., E.T.D., L.C.S., K.M., A.H.B.), and Division of Newborn Medicine (P.B.A.), Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Physiology and Sarver Molecular Cardiovascular Research Program (C.H., H.G.), University of Arizona, Tucson; Center for Computational Molecular Biology and Department of Molecular and Cellular Biology and Biochemistry (R.S., W.G.F.), Brown University, Providence, RI; Department of Translational Medicine (N.V., J.L.), IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France; Departments of Pediatrics and Neurology and Neurotherapeutics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (P.B.S.), University of California, Los Angeles; Division of Human Genetics (N.S.), Department of Pediatrics, Rhode Island Hospital, Providence; Department of Pediatrics, Division of Pediatric Pathology (J.M.D.), and Department of Pathology and Laboratory Medicine (M.W.L), Medical College of Wisconsin, Milwaukee; Hasbro Children's Hospital (J.M.D.), and Center for Biomedical Engineering (W.G.F.), Brown University, Providence, RI.
authors: Ozge
authors: O
authors: Ceyhan-Birsoy
authors: Pankaj B
authors: PB
authors: Agrawal
authors: Carlos
authors: C
authors: Hidalgo
authors: Klaus
authors: K
authors: Schmitz-Abe
authors: Elizabeth T
authors: ET
authors: DeChene
authors: Lindsay C
authors: LC
authors: Swanson
authors: Rachel
authors: R
authors: Soemedi
authors: Nasim
authors: N
authors: Vasli
authors: Susan T
authors: ST
authors: Iannaccone
authors: Perry B
authors: PB
authors: Shieh
authors: Natasha
authors: N
authors: Shur
authors: Jane M
authors: JM
authors: Dennison
authors: Michael W
authors: MW
authors: Lawlor
authors: Jocelyn
authors: J
authors: Laporte
authors: Kyriacos
authors: K
authors: Markianos
authors: William G
authors: WG
authors: Fairbrother
authors: Henk
authors: H
authors: Granzier
authors: Alan H
authors: AH
authors: Beggs
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D064211:Connectin / Q000235:genetics*; D034285:Dynamin II / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D020914:Myopathies, Structural, Congenital / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D016037:Single-Blind Method; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D064211:Connectin; D009687:Nuclear Proteins; C577285:TTN protein, human; D025521:Tumor Suppressor Proteins; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin; D034285:Dynamin II
references: Cell. 1995 Apr 7;81(1):27-40
references: 7720071
references: Nucleic Acids Res. 2001 Jan 1;29(1):308-11
references: 11125122
references: Cell. 2004 Dec 17;119(6):831-45
references: 15607979
references: Semin Pediatr Neurol. 2011 Dec;18(4):250-6
references: 22172420
references: Circ Res. 2011 Sep 30;109(8):858-66
references: 21835910
references: Hum Mol Genet. 2008 Nov 1;17(21):3271-80
references: 18676612
references: Nat Genet. 2002 Feb;30(2):201-4
references: 11788824
references: Nat Genet. 2005 Nov;37(11):1207-9
references: 16227997
references: Am J Hum Genet. 2002 Sep;71(3):492-500
references: 12145747
references: FASEB J. 2011 Mar;25(3):822-9
references: 21115852
references: Neurology. 2005 Feb 22;64(4):636-42
references: 15728284
references: Circ Res. 2001 Nov 23;89(11):1065-72
references: 11717165
references: J Mol Med (Berl). 2006 Jun;84(6):478-83
references: 16733766
references: Am J Hum Genet. 1998 Mar;62(3):620-6
references: 9497249
references: Hum Mol Genet. 1999 Jul;8(7):1329-36
references: 10369880
references: Biochem Biophys Res Commun. 2002 Feb 22;291(2):385-93
references: 11846417
references: Acta Neuropathol. 2009 Mar;117(3):283-91
references: 19084976
references: Adv Exp Med Biol. 2010;682:105-22
references: 20824522
references: J Cell Biol. 2000 Dec 25;151(7):1583-90
references: 11134085
references: Brain. 2012 Jun;135(Pt 6):1682-94
references: 22577218
references: Brain. 2012 Jun;135(Pt 6):1695-713
references: 22577215
references: J Cell Sci. 2000 Apr;113 ( Pt 8):1405-14
references: 10725223
references: Ann Neurol. 2010 Nov;68(5):717-26
references: 20839240
references: Neuromuscul Disord. 2010 Apr;20(4):223-8
references: 20181480
references: J Anim Sci. 1995 Apr;73(4):1064-73
references: 7628949
references: Hum Mol Genet. 2009 Jul 1;18(13):2359-69
references: 19346529
references: Am J Hum Genet. 2004 Oct;75(4):703-8
references: 15322983
references: Ann Neurol. 2007 Apr;61(4):340-51
references: 17444505
references: Eur J Hum Genet. 2012 Oct;20(10):
references: 22617344
references: Neuromuscul Disord. 2008 Dec;18(12):922-8
references: 18948003
references: Hum Mutat. 2012 Jun;33(6):949-59
references: 22396310
references: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3444-9
references: 17360664
references: Nat Genet. 2000 Feb;24(2):163-6
references: 10655062
references: Neurology. 2001 Apr 10;56(7):869-77
references: 11294923
references: Circ Res. 2004 Feb 20;94(3):284-95
references: 14976139
references: N Engl J Med. 2012 Feb 16;366(7):619-28
references: 22335739
references: Adv Protein Chem. 2005;71:89-119
references: 16230110
references: Cardiovasc Res. 2008 Mar 1;77(4):637-48
references: 17475230
references: Orphanet J Rare Dis. 2008 Sep 25;3:26
references: 18817572
references: Skelet Muscle. 2011 Jul 13;1(1):26
references: 21797990