Charcot-Marie-Tooth type 4B2 demyelinating neuropathy in miniature Schnauzer dogs caused by a novel splicing
Animal model
Canine
Charcot-Marie-Tooth diseases
Demyelinating neuropathy
Genetic variant
Genome wide association screen
Inherited polyneuropathy
Myotubularine related proteins
SET-binding factor 2
Spontaneous disease
Journal
PeerJ
ISSN: 2167-8359
Titre abrégé: PeerJ
Pays: United States
ID NLM: 101603425
Informations de publication
Date de publication:
2019
2019
Historique:
received:
10
06
2019
accepted:
02
10
2019
entrez:
28
11
2019
pubmed:
28
11
2019
medline:
28
11
2019
Statut:
epublish
Résumé
Charcot-Marie-Tooth (CMT) disease is the most common neuromuscular disorder in humans affecting 40 out of 100,000 individuals. In 2008, we described the clinical, electrophysiological and pathological findings of a demyelinating motor and sensory neuropathy in Miniature Schnauzer dogs, with a suspected autosomal recessive mode of inheritance based on pedigree analysis. The discovery of additional cases has followed this work and led to a genome-wide association mapping approach to search for the underlying genetic cause of the disease. For genome wide association screening, genomic DNA samples from affected and unaffected dogs were genotyped using the Illumina CanineHD SNP genotyping array. The genome-wide association study gave an indicative signal on canine chromosome 21. Although the signal was not of genome-wide significance due to the small number of cases, the This study reports the first genetic variant in Miniature Schnauzer dogs responsible for the occurrence of a demyelinating peripheral neuropathy with abnormally folded myelin. This discovery establishes a genotype/phenotype correlation in affected Miniature Schnauzers that can be used for the diagnosis of these dogs. It further supports the dog as a natural model of a human disease; in this instance, Charcot-Marie-Tooth disease. It opens avenues to search the biological mechanisms responsible for the disease and to test new therapies in a non-rodent large animal model. In particular, recent gene editing methods that led to the restoration of dystrophin expression in a canine model of muscular dystrophy could be applied to other canine models such as this before translation to humans.
Sections du résumé
BACKGROUND
BACKGROUND
Charcot-Marie-Tooth (CMT) disease is the most common neuromuscular disorder in humans affecting 40 out of 100,000 individuals. In 2008, we described the clinical, electrophysiological and pathological findings of a demyelinating motor and sensory neuropathy in Miniature Schnauzer dogs, with a suspected autosomal recessive mode of inheritance based on pedigree analysis. The discovery of additional cases has followed this work and led to a genome-wide association mapping approach to search for the underlying genetic cause of the disease.
METHODS
METHODS
For genome wide association screening, genomic DNA samples from affected and unaffected dogs were genotyped using the Illumina CanineHD SNP genotyping array.
RESULTS
RESULTS
The genome-wide association study gave an indicative signal on canine chromosome 21. Although the signal was not of genome-wide significance due to the small number of cases, the
CONCLUSIONS
CONCLUSIONS
This study reports the first genetic variant in Miniature Schnauzer dogs responsible for the occurrence of a demyelinating peripheral neuropathy with abnormally folded myelin. This discovery establishes a genotype/phenotype correlation in affected Miniature Schnauzers that can be used for the diagnosis of these dogs. It further supports the dog as a natural model of a human disease; in this instance, Charcot-Marie-Tooth disease. It opens avenues to search the biological mechanisms responsible for the disease and to test new therapies in a non-rodent large animal model. In particular, recent gene editing methods that led to the restoration of dystrophin expression in a canine model of muscular dystrophy could be applied to other canine models such as this before translation to humans.
Identifiants
pubmed: 31772832
doi: 10.7717/peerj.7983
pii: 7983
pmc: PMC6875392
doi:
Types de publication
Journal Article
Langues
eng
Pagination
e7983Subventions
Organisme : Medical Research Council
ID : G108/638
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0802760
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1001253
Pays : United Kingdom
Organisme : The Dunhill Medical Trust
ID : R605/0717
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S01165X/1
Pays : United Kingdom
Informations de copyright
©2019 Granger et al.
Déclaration de conflit d'intérêts
Drs Sally Ricketts, Rebekkah Hitti and Oliver Forman are employed by the Animal Health Trust, and Dr Nicolas Granger is employed by Bristol Veterinary Specialists, CVS Referrals.
Références
PLoS Genet. 2016 Dec 29;12(12):e1006482
pubmed: 28033318
Traffic. 2008 Aug;9(8):1240-9
pubmed: 18429927
Curr Top Microbiol Immunol. 2012;362:209-33
pubmed: 23086420
Hum Mol Genet. 2005 Dec 1;14(23):3685-95
pubmed: 16249189
J Vet Intern Med. 2016 May;30(3):813-8
pubmed: 26968732
BMC Genet. 2016 Aug 26;17(1):123
pubmed: 27566131
Ann Neurol. 2013 Sep;74(3):391-6
pubmed: 23913540
G3 (Bethesda). 2015 Nov 23;6(2):255-62
pubmed: 26596647
Neurobiol Dis. 2016 Feb;86:75-85
pubmed: 26607784
Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4916-21
pubmed: 18349142
Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):927-32
pubmed: 16410353
PLoS One. 2013;8(2):e54547
pubmed: 23393557
Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):15060-5
pubmed: 12391329
Vet Clin North Am Small Anim Pract. 2004 Nov;34(6):1361-401
pubmed: 15474679
Trends Genet. 2001 Apr;17(4):221-8
pubmed: 11275328
Neuromuscul Disord. 1991;1(1):19-29
pubmed: 1822774
J Biol Chem. 2005 Sep 9;280(36):31699-707
pubmed: 15998640
J Peripher Nerv Syst. 2011 Mar;16(1):1-14
pubmed: 21504497
Neurology. 2004 Oct 26;63(8):1527-9
pubmed: 15505184
J Thromb Thrombolysis. 2013 Nov;36(4):501-6
pubmed: 23334996
Lancet Neurol. 2009 Jul;8(7):654-67
pubmed: 19539237
J Peripher Nerv Syst. 2013 Jun;18(2):192-4
pubmed: 23781969
BMC Genomics. 2017 Aug 25;18(1):662
pubmed: 28841859
Neuromolecular Med. 2006;8(1-2):217-42
pubmed: 16775378
PLoS Genet. 2009 May;5(5):e1000499
pubmed: 19492087
Brain. 2011 Sep;134(Pt 9):2664-76
pubmed: 21840889
PLoS One. 2015 Feb 06;10(2):e0117055
pubmed: 25659135
Neuromuscul Disord. 2002 Nov;12(9):869-73
pubmed: 12398840
Mol Biol Cell. 2012 Jul;23(14):2723-40
pubmed: 22648168
Clin Genet. 2018 Nov;94(5):467-472
pubmed: 30028002
Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R285-92
pubmed: 12925573
Am J Hum Genet. 2003 May;72(5):1141-53
pubmed: 12687498
Nat Rev Neurosci. 2003 Sep;4(9):714-26
pubmed: 12951564
Neurology. 2004 Aug 10;63(3):577-80
pubmed: 15304601
Hum Genet. 2003 Feb;112(2):135-42
pubmed: 12522554
PLoS One. 2010 Jun 22;5(6):e11258
pubmed: 20582309
Curr Opin Neurol. 2013 Oct;26(5):473-80
pubmed: 23945280
J Neurol Sci. 2008 Dec 15;275(1-2):100-5
pubmed: 18809183
Mol Biol Cell. 2004 Jan;15(1):189-96
pubmed: 14565969
Neuromolecular Med. 2006;8(1-2):43-62
pubmed: 16775366
Nucleic Acids Res. 2012 Aug;40(15):e115
pubmed: 22730293
Acta Myol. 2014 Dec;33(3):144-8
pubmed: 25873783
J Neurol Sci. 2013 Nov 15;334(1-2):176-9
pubmed: 23962696
Brain. 2004 Nov;127(Pt 11):2540-50
pubmed: 15469949
Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14697-702
pubmed: 20682747
Nat Genet. 2000 May;25(1):17-9
pubmed: 10802647
G3 (Bethesda). 2016 Sep 08;6(9):2687-92
pubmed: 27527794
Brain. 2001 May;124(Pt 5):907-15
pubmed: 11335693
Curr Biol. 2003 Mar 18;13(6):504-9
pubmed: 12646134
Hum Mol Genet. 2007 Dec 15;16(24):2991-3001
pubmed: 17855448
Gene Expr Patterns. 2006 Oct;6(8):978-84
pubmed: 16750429
Expert Rev Mol Med. 2007 Sep 20;9(25):1-16
pubmed: 17880751
Genomics Proteomics Bioinformatics. 2014 Oct;12(5):221-7
pubmed: 25462154
Neuromuscul Disord. 2011 Aug;21(8):543-50
pubmed: 21741241
Neurology. 2004 Oct 12;63(7):1327-8
pubmed: 15477569
J Biol Chem. 2002 Feb 8;277(6):4526-31
pubmed: 11733541
Hum Mol Genet. 2000 Sep 22;9(15):2223-9
pubmed: 11001925
Brain. 1990 Dec;113 ( Pt 6):1629-43
pubmed: 2276038
Hum Mol Genet. 2013 Apr 15;22(8):1493-506
pubmed: 23297362
PLoS One. 2013 May 31;8(5):e64627
pubmed: 23741357
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Physiology (Bethesda). 2009 Feb;24:8-16
pubmed: 19196647
Clin Genet. 1974;6(2):98-118
pubmed: 4430158
J Vet Intern Med. 2018 Nov;32(6):2082-2087
pubmed: 30307654
Hum Mol Genet. 2003 Feb 1;12(3):349-56
pubmed: 12554688
Mol Biotechnol. 1996 Jun;5(3):233-41
pubmed: 8837029
Vet J. 2011 Jun;188(3):274-85
pubmed: 20638305
J Peripher Nerv Syst. 2018 Dec;23(4):216-226
pubmed: 29896895
Muscle Nerve. 1989 Jul;12(7):568-75
pubmed: 2779605
Science. 2018 Oct 5;362(6410):86-91
pubmed: 30166439
PLoS Genet. 2014 Oct 02;10(10):e1004635
pubmed: 25275565
Biochem Biophys Res Commun. 2002 Feb 22;291(2):305-12
pubmed: 11846405
Hum Mol Genet. 2006 Feb 15;15(4):569-79
pubmed: 16399794