1. Canine Neuronal Ceroid Lipofuscinoses as Models for
Understanding Disease Mechanisms and Developing
Therapies for the Human NCLs
Martin L. Katz1,2, Gary S. Johnson3, Joan R. Coates2, and Dennis P. O’Brien2
Departments of 1Ophthalmology, 2Veterinary Medicine & Surgery, and 3Veterinary Pathobiology
University of Missouri, Columbia, Missouri, USA
Mutations in Eight Different Genes
Have Been Associated with
NCLs in Dogs
English Setter
American Bulldog
Border Collie
Longhaired
Dachshund
Longhaired
Dachshund
Australian Shepherd
Mutation: CLN6 missense
Corresponding human disease: CLN6, late
infantile/early juvenile variant
Reference: Katz ML. Farias FH. Sanders DN. Zeng
R. Khan S. Johnson GS. O'Brien DP. J.Biomed,
Biotech. 2011:198042, 2011.
Tibetan Terrier
Mutation: CLN5 nonsense
Corresponding human
disease: CLN5, variable
Reference: Melville SA. Wilson CL.
Chiang CS. Studdert VP. Lingaas F.
Wilton AN. Genomics. 86:287-94,
2005.
Mutation: ATP13A2
deletion
Corresponding human
disease: PARK9
Reference:Farias FH, Zeng R
Johnson GS, Wininger FA, Taylor
JF, Schnabel RD, McKay SD, Lohi
H, Lindblad-Toh K, Wade CM,
O’Brien DP, Katz ML. Neurobiol.
Dis. 42:468-474, 2011.
Mutation: PPT1 insertion
Corresponding human
disease: CLN1, classical
infantile
Reference: Sanders DN. Farias FH.
Johnson GS. Chiang V. Cook JR.
O'Brien DP. Hofmann SL. Lu JY.
Katz ML. Molec. Genet. Metab.
100:349-56, 2010.
Mutation: MFSD8 deletion
Corresponing human
disease: CLN7, variant
late infantile
Reference: Guo J, O’Brien DP,
Mhlanga-Mutangadura T, Olby NJ,
Taylor JF, Schnabel RD, Katz ML,
Johnson GS. Unpublushed, 2014.
Pathways to NCL Mutation
Discovery in Dogs
Development of a
Dachshund Model for
Therapy Development for
Late-Infantile NCL
Dog with Signs Suggestive of NCL
Symptom Questionnaire and
Pedigree Information
Histopathological Confirmation of NCL
Candidate Gene Analysis
using Whole Genome
Sequencing
Putative
Mutation
Identification
Collect DNA and
Phenotype Information
from Dogs of the Same
Breed
Identification of
Candidate Locus
Sequence
Positional
Candidate Genes
Putative Mutation
Identification
Confirmation of
Causative Mutation
by Association
Analysis and
Enzyme Activity
Assays
Acknowledgements
This research was made possible by financial support
from the Batten Disease and Support and Research
Association and the American Kennel Club Canine
Health Foundation. The dedicated support and
cooperation of numerous dog owners and breed clubs
played a key role in the success of this research.
Linkage Analysis
and/or
Homozygosity
Mapping
Longhaired
Dachshund with
signs of NCL died in
Pennsylvania.
Tissues were shipped
to Univ. of Missouri
for analysis.
NCL was
confirmed with
fluorescence
and electron
microscopy.
EM suggested CLN2 (TPP1)
as a candidate gene.
Sequence analysis
identified a
mutation in TPP1.
Pedigree led to a breeder in
southern Missouri who still
owned both parents.
Parents were confirmed to be
carriers of the mutation, were
obtained by the University of
Missouri, and were bred to
initiate a research colony.
Studies are now under way to use this dog model
to develop treatments for late-infantile NCL
Gene Therapy
Enzyme
Replacement
Therapy
Stem Cell
Therapy
Martin L. Katz, Ph.D.
Lead Investigator
Professor of Ophthalmology,
Genetics and Neurobiology
University of Missouri,
Columbia, MO
USA
Mutation: CLN8 missense
Corresponding human
disease: CLN8, late
infantile variant
Reference: Katz ML. Khan S.
Awano T. Shahid SA. Siakotos AN.
Johnson GS. Biochem. Biophys.
Res. Commun. 327:541-7, 2005.
Mutation: TPP1 frameshift
Corresponding human
disease: CLN2, classical
late infantile
Reference: Awano T. Katz ML.
O'Brien DP. Sohar I. Lobel P.
Coates JR. Khan S. Johnson GC.
Giger U. Johnson GS. Molec.
Genet. Metab. 89:254-60, 2006.
Mutation: CTSD missense
Corresponding human
disease: CLN10, variable
Reference:Awano T. Katz ML.
O'Brien DP. Taylor JF. Evans J.
Khan S. Sohar I. Lobel P. Johnson
GS. Molec. Genet. Metab. 87:341-
8, 2006.
Large animal models of the NCLs can greatly help us to
develop better understanding of the mechanisms underlying
these diseases and to test therapies for potential human
applications. Naturally occurring mutations cause NCL in
many dog breeds. The identification of these mutations can
lead to the establishment of dog models that can be used in
therapeutic studies. At present, only the Dachshund model
for late infantile NCL is being used for therapy development.
Ongoing studies with this model are likely to result in an
effective treatment for children with this disease in the near
future.
Normal
Carrier
Affected
One base deletion
resulting in frameshift
Lay Summary
Mutation: CLN8 nonsense
Corresponding human disease: CLN8, late
infantile variant
Reference: Guo J, Johnson GS, Brown HA,
Provencher ML, da Costa RC, Mhlanga-
Mutangadura T, Taylor JF, Schnabel RD, O’Brien DP,
Katz ML. Molec Genet Metabol, online
prepublication 4-JUN-2014.
Chinese Crested