title: Neuronal ceroid lipofuscinosis associated with an MFSD8 mutation in Chihuahuas.
abstract: The neuronal ceroid lipofuscinoses (NCLs) are hereditary neurodegenerative disorders characterized by progressive declines in neurological functions, seizures, and premature death. NCLs result from mutations in at least 13 different genes. Canine versions of the NCLs can serve as important models in developing effective therapeutic interventions for these diseases. NCLs have been described in a number of dog breeds, including Chihuahuas. Studies were undertaken to further characterize the pathology of Chihuahua NCL and to verify its molecular genetic basis. Four unrelated client owned Chihuahuas from Japan, Italy and England that exhibited progressive neurological signs consistent with a diagnosis of NCL underwent neurological examinations. Brain and in some cases also retinal and heart tissues were examined postmortem for the presence of lysosomal storage bodies characteristic of NCL. The affected dogs exhibited massive accumulation of autofluorescent lysosomal storage bodies in the brain, retina and heart accompanied by brain atrophy and retinal degeneration. The dogs were screened for known canine NCL mutations previously reported in a variety of dog breeds. All 4 dogs were homozygous for the MFSD8 single base pair deletion (MFSD8:c.843delT) previously associated with NCL in a Chinese Crested dog and in 2 affected littermate Chihuahuas from Scotland. The dogs were all homozygous for the normal alleles at the other genetic loci known to cause different forms of canine NCL. The MFSD8:c.843delT mutation was not present in 57 Chihuahuas that were either clinically normal or suffered from unrelated diseases or in 1761 unaffected dogs representing 186 other breeds. Based on these data it is almost certain that the MFSD8:c.843delT mutation is the cause of NCL in Chihuahuas. Because the disorder occurred in widely separated geographic locations or in unrelated dogs from the same country, it is likely that the mutant allele is widespread among Chihuahuas. Genetic testing for this mutation in other Chihuahuas is therefore likely to identify intact dogs with the mutant allele that could be used to establish a research colony that could be used to test potential therapeutic interventions for the corresponding human disease.
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia MO, USA.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Ashwini
authors.affiliation: Department of Veterinary Science, School of Veterinary Medicine, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Angelo
authors.affiliation: Department of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamato
authors.affiliation: Department of Veterinary Science, School of Veterinary Medicine, Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Department of Veterinary Science, School of Veterinary Medicine, Turin, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Cagnotti
authors.affiliation: Langford Veterinary Services, Bristol, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Harcourt-Brown
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia MO, USA.
authors.forename: Tendai
authors.initials: T
authors.lastname: Mhlanga-Mutangadura
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia MO, USA.
authors.forename: Juyuan
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia MO, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Johnson
authors.affiliation: Department of Ophthalmology, University of Missouri School of Medicine, Columbia, MO, USA. Electronic address: katzm@health.missouri.edu.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Katz
mesh_terms: D000818:Animals; D001921:Brain / Q000503:physiopathology; D001947:Breeding; D004283:Dog Diseases / Q000235:genetics* / Q000503:physiopathology; D004285:Dogs; D006720:Homozygote; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000503:physiopathology / Q000662:veterinary; D012160:Retina / Q000503:physiopathology; D017384:Sequence Deletion
chemical_list: D026901:Membrane Transport Proteins
keywords: Batten disease; CLN7; Canine model; Lysosomal storage disease; Neurodegenerative disease; Retinal degeneration