The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

被引:27
作者
Faller, Kiterie M. E. [1 ]
Bras, Jose [2 ]
Sharpe, Samuel J. [1 ]
Anderson, Glenn W. [3 ]
Darwent, Lee [2 ]
Kun-Rodrigues, Celia [2 ]
Alroy, Joseph [4 ,5 ]
Penderis, Jacques [6 ]
Mole, Sara E. [7 ,8 ]
Gutierrez-Quintana, Rodrigo [1 ]
Guerreiro, Rita J. [2 ]
机构
[1] Univ Glasgow, Coll Med Vet & Life Sci, Sch Vet Med, Bearsden Rd, Glasgow G61 1QH, Lanark, Scotland
[2] UCL, Inst Neurol, Dept Mol Neurosci, London, England
[3] Great Ormond St Hosp Sick Children, Dept Histopathol, London, England
[4] Tufts Univ, Sch Med, Dept Pathol, Boston, MA 02111 USA
[5] Tufts Univ New England Med Ctr, Boston, MA 02111 USA
[6] VetExtra Neurol, Stirling, Scotland
[7] UCL, Inst Child Hlth, MRC Lab Mol Cell Biol, London, England
[8] UCL, Dept Genet Evolut & Environm, London, England
关键词
MFSD8; lysosomal storage disorder; neurodegeneration; DNA-SEQUENCING DATA; MUTATION; GENOME; GENE; MICE; MUCOPOLYSACCHARIDOSIS; FRAMEWORK; TOOLKIT;
D O I
10.1002/jnr.23710
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Neuronal ceroid lipofuscinoses (NCLs) are a group of incurable lysosomal storage disorders characterized by neurodegeneration and accumulation of lipopigments mainly within the neurons. We studied two littermate Chihuahua dogs presenting with progressive signs of blindness, ataxia, pacing, and cognitive impairment from 1 year of age. Because of worsening of clinical signs, both dogs were euthanized at about 2 years of age. Postmortem examination revealed marked accumulation of autofluorescent intracellular inclusions within the brain, characteristic of NCL. Whole-genome sequencing was performed on one of the affected dogs. After sequence alignment and variant calling against the canine reference genome, variants were identified in the coding region or splicing regions of four previously known NCL genes (CLN6, ARSG, CLN2 [=TPP1], and CLN7 [=MFSD8]). Subsequent segregation analysis within the family (two affected dogs, both parents, and three relatives) identified MFSD8:p.Phe282Leufs13*, which had previously been identified in one Chinese crested dog with no available ancestries, as the causal mutation. Because of the similarities of the clinical signs and histopathological changes with the human form of the disease, we propose that the Chihuahua dog could be a good animal model of CLN7 disease. (c) 2016 Wiley Periodicals, Inc.
引用
收藏
页码:339 / 347
页数:9
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