title: A novel locus for episodic ataxia:UBR4 the likely candidate.
abstract: Episodic ataxias (EAs) are rare neurological channelopathies that are characterized by spells of imbalance and a lack of co-ordination. There are seven clinically recognized EAs and multiple isolated cases. Five disease-causing genes have been identified to date. We describe a novel form of autosomal dominant EA in a large three-generation Irish family. This form of EA presents in early childhood with periods of unsteadiness generalized weakness and slurred speech during an attack, which may be triggered by physical tiredness or stress. Linkage analysis undertaken in 13 related individuals identified a single disease locus (1p36.13-p34.3) with a LOD score of 3.29. Exome sequencing was performed. Following data analysis, which included presence/absence within the linkage peak, two candidate variants were identified. These are located in the HSPG2 and UBR4 genes. UBR4 is an ubiquitin ligase protein that is known to interact with calmodulin, a Ca(2+) protein, in the cytoplasm. It also co-localizes with ITPR1 a calcium release channel that is a major determinant of mammal co-ordination. Although UBR4 is not an ion channel gene, the potential for disrupted Ca(2+) control within neuronal cells highlights its potential for a role in this form of EA.
authors: Temple Street Children's University Hospital, Temple Street, Dublin, Ireland.
authors: Judith
authors: J
authors: Conroy
authors: University College Dublin, Belfield, Dublin, Ireland.
authors: Paul
authors: P
authors: McGettigan
authors: The Adelaide and Meath Hospital, incorporating the National Children's Hospital (AMNCH), Tallaght, Dublin, Ireland.
authors: Raymond
authors: R
authors: Murphy
authors: Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
authors: David
authors: D
authors: Webb
authors: The Adelaide and Meath Hospital, incorporating the National Children's Hospital (AMNCH), Tallaght, Dublin, Ireland.
authors: Sinéad M
authors: SM
authors: Murphy
authors: Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
authors: Blathnaid
authors: B
authors: McCoy
authors: The Adelaide and Meath Hospital, incorporating the National Children's Hospital (AMNCH), Tallaght, Dublin, Ireland.
authors: Christine
authors: C
authors: Albertyn
authors: Temple Street Children's University Hospital, Temple Street, Dublin, Ireland.
authors: Dara
authors: D
authors: McCreary
authors: The Adelaide and Meath Hospital, incorporating the National Children's Hospital (AMNCH), Tallaght, Dublin, Ireland.
authors: Cara
authors: C
authors: McDonagh
authors: Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
authors: Orla
authors: O
authors: Walsh
authors: 1] Temple Street Children's University Hospital, Temple Street, Dublin, Ireland [2] Our Lady's Children's Hospital, Crumlin, Dublin, Ireland [3] National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland.
authors: Sallyann
authors: S
authors: Lynch
authors: 1] University College Dublin, Belfield, Dublin, Ireland [2] The Academic Centre on Rare Diseases, University College Dublin, Belfield, Dublin, Ireland.
authors: Sean
authors: S
authors: Ennis
mesh_terms: D000293:Adolescent; D000328:Adult; D001259:Ataxia / Q000175:diagnosis / Q000235:genetics; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002882:Chromosomes, Human, Pair 13; D003598:Cytoskeletal Proteins / Q000235:genetics*; D059472:Exome; D005260:Female; D056426:Genetic Loci; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics; D007494:Ireland; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases; D055815:Young Adult
chemical_list: D002148:Calmodulin-Binding Proteins; D003598:Cytoskeletal Proteins; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; C505833:UBR4 protein, human; D044767:Ubiquitin-Protein Ligases
references: Mol Immunol. 2008 May;45(9):2660-6
references: 18261799
references: Trends Pharmacol Sci. 2006 Feb;27(2):78-84
references: 16412523
references: Neurology. 2012 Nov 20;79(21):2115-21
references: 23077024
references: J Biol Chem. 1998 Feb 13;273(7):3954-62
references: 9461582
references: Neuron. 2003 Sep 11;39(6):951-60
references: 12971895
references: Hum Mutat. 2006 Nov;27(11):1082-91
references: 16927315
references: Cell. 1995 Nov 3;83(3):433-42
references: 8521473
references: Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15093-8
references: 16214886
references: Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16454-9
references: 16263935
references: Proc Natl Acad Sci U S A. 1984 May;81(10):3118-22
references: 6328498
references: Nat Protoc. 2009;4(7):1073-81
references: 19561590
references: PLoS Genet. 2007 Jun;3(6):e108
references: 17590087
references: Bioinformatics. 2009 Jul 15;25(14):1754-60
references: 19451168
references: Neurology. 2004 Jan 13;62(1):17-22
references: 14718690
references: Bioinformatics. 2005 Jul 15;21(14):3176-8
references: 15879453
references: Cell Mol Life Sci. 2009 Nov;66(21):3421-34
references: 19629389
references: Neurology. 2010 Oct 19;75(16):1454-8
references: 20956790
references: Front Neurol. 2011 Sep 09;2:51
references: 21927611
references: J Med Genet. 2006 Jun;43(6):527-30
references: 16236810
references: Acta Neurol Scand. 2008 Aug;118(2):69-86
references: 18384456
references: J Korean Med Sci. 2001 Dec;16(6):809-13
references: 11748369
references: Genome Res. 2010 Sep;20(9):1297-303
references: 20644199
references: Epilepsia. 2012 Dec;53(12):e196-9
references: 23126439
references: Cell. 2005 Sep 23;122(6):957-68
references: 16169070
references: Nat Genet. 2000 Dec;26(4):480-3
references: 11101850
references: Nucleic Acids Res. 2010 Sep;38(16):e164
references: 20601685
references: Muscle Nerve. 2006 Sep;34(3):292-7
references: 16770776
references: Nat Genet. 2002 Jan;30(1):97-101
references: 11731797
references: Nucleic Acids Res. 2007;35(11):3823-35
references: 17526529
references: J Neurosci. 2008 Apr 2;28(14):3604-14
references: 18385319
references: J Neurosci. 2004 Apr 21;24(16):4030-42
references: 15102918
references: Sci STKE. 2005 Dec 20;2005(315):re15
references: 16369047
references: Ther Adv Neurol Disord. 2011 May;4(3):183-91
references: 21694818
references: Audiol Neurootol. 1997 Nov-Dec;2(6):373-83
references: 9390841
references: Neurology. 2005 Jul 12;65(1):156-8
references: 16009908
references: Trends Neurosci. 2010 May;33(5):211-9
references: 20226542
references: Nat Methods. 2010 Apr;7(4):248-9
references: 20354512
references: Early Hum Dev. 1999 Mar;54(2):103-16
references: 10213289
references: Brain Dev. 1998 Jan;20(1):9-13
references: 9533553
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Eur J Neurosci. 2011 Apr;33(8):1493-503
references: 21410792
references: Neurology. 2005 Aug 23;65(4):529-34
references: 16116111
references: Nat Genet. 2001 Apr;27(4):431-4
references: 11279527
references: Bioinformatics. 2009 Aug 15;25(16):2078-9
references: 19505943
references: Nature. 2001 May 24;411(6836):484-9
references: 11373682
references: Genetics. 2005 Nov;171(3):1239-46
references: 16118194
references: Am J Hum Genet. 2000 May;66(5):1531-9
references: 10762541