A mutation in the cathepsin D gene (CTSD) in American Bulldogs with neuronal ceroid lipofuscinosis

被引:106
作者
Awano, T
Katz, ML
O'Brien, DP
Taylor, JF
Evans, J
Khan, S
Sohar, I
Lobel, P
Johnson, GS [1 ]
机构
[1] Univ Missouri, Coll Vet Med, Dept Vet Pathobiol, Columbia, MO 65211 USA
[2] Univ Missouri, Sch Med, Mason Eye Inst, Columbia, MO USA
[3] Univ Missouri, Coll Vet Med, Dept Vet Med & Surg, Columbia, MO USA
[4] Univ Missouri, Coll Agr Food & Nat Resources, Div Anim Sci, Columbia, MO USA
[5] Vet Neurol Ctr, Phoenix, AZ USA
[6] Univ Med & Dent New Jersey, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA
[7] Univ Med & Dent New Jersey, Dept Pharmacol, Piscataway, NJ 08854 USA
关键词
neuronal ceroid lipofuscinosis; CTSD; cathepsin D; canine; missense mutation;
D O I
10.1016/j.ymgme.2005.11.005
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We obtained DNA, brains, and eyes from American Bulldogs with neurodegeneration due to neuronal ceroid lipofuscinosis (NCL). The diagnosis of NCL was confirmed by detection of autofluorescent cytoplasmic inclusions within neurons throughout the brains, in retinal ganglion cells, and along outer limiting membranes of the retinas. Electron microscopy revealed that the inclusions had coarsely granular matrices Surrounding well-delineated spherical structures and that the inclusions near the retinal outer limiting membranes were within photoreceptor cells, mostly cones. Affected American Bulldogs were homozygous for the A allele of a G to A transition ill the cathepsin D gene (CTSD), which predicts the conversion of methionine-199 to all isoleucine. Only the G allele was detected in DNA samples from 131 randomly selected dogs representing 108 breeds other than American Bulldog; however, the A allele had a frequency of 0.28 among 123 genotyped American Bulldogs. Transmission analysis in a 99 dog pedigree of American Bulldogs indicated a probability of less than 10(-7) that alleles from any mutation unlinked to CTSD would be concordant with the pedigree and phenotypes of the dogs. Brain samples from affected dogs had 36% of the cathepsin D-specific enzymatic activity found in control dog brains; whereas, specific enzymatic activities of 15 other lysosomal enzymes were unchanged or increased. Compared to previously described NCLs in mice and sheep that completely lack cathepsin D activity, the clinical course of NCL in the American Bulldogs was less severe and more closely resembled that of many human NCLs. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:341 / 348
页数:8
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