OMIA:002591-9615 : Lysosomal storage disease, CNP-related in Canis lupus familiaris (dog)

Categories: Lysosomal storage disease

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 619071 (gene) , 123830 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2022

Species-specific description: Bullock et al. (2022) report a progressive neurological disorder in purebred Dalmatian dogs with similarities to the neuronal ceroid lipofuscinoses. Keller et al. (2024) report a Weimaraner with the same condition caused by a different variant in the CNP gene.

Molecular basis: Bullock et al. (2022): “ Whole genome sequences, generated with DNA from the two euthanized Dalmatians, both contained a rare, homozygous single-base deletion and reading-frame shift in CNP … . The late-onset disease was exhibited by five of seven related Dalmatians that were heterozygous for the deletion allele and over 8 years of age, whereas none of 16 age-matched reference-allele homozygotes developed neurologic signs.”
Keller et al. (2024): "whole genome sequence generated from the affected [Weimaraner] dog contained a homozygous G-to-A missense mutation in CNP, which encodes proteins with CNPase enzyme activity and a structural role in myelin. The mutation predicts a Thr42Met amino acid sequence substitution. Genotyping of archived Weimaraner DNA samples identified an additional G > A variant homozygote with a clinical history and brain lesions similar to those of the proband. Of 304 Weimaraners and over 4000 other dogs of various breeds, the proband and the other Weimaraner that exhibited similar signs were the only two that were homozygous for the CNP missense variant."

Clinical features: Bullock et al. (2022): “The disease [in Dalmatians] is characterized by anxiety, pacing and circling, hypersensitivity, cognitive decline, sleep disturbance, loss of coordination, loss of control over urination and defecation, and visual impairment. Neurological signs first became apparent when the dogs were approximately 18 months of age and progressed slowly. Two affected littermates were euthanized at approximately 7 years, 5 months and 8 years, 2 months of age due to the severity of neurological impairment. The mother of the affected dogs and four other relatives exhibited milder, later-onset neurological signs.”
Keller et al. (2024) report a male Weimaraner: "Clinical signs included fecal incontinence, lethargy, moderate paraparesis, proprioceptive pelvic limb ataxia, falling, cognitive decline, incoordination, decreased interest in food, changes in posture, and episodes of trance-like behavior. Neurologic signs were first observed at approximately 4 years, 10 months of age and progressed slowly. Magnetic resonance imaging showed generalized brain atrophy with areas of white matter pathology. Humane euthanasia was elected at 6 years, 7 months of age due to increasing severity of the neurological signs"

Pathology: Bullock et al. (2022): “Pronounced accumulations of autofluorescent intracellular inclusions were found in cerebral cortex, cerebellum, optic nerve, and cardiac muscle of the affected [Dalmatian] dogs. These inclusions co-localized with immunolabeling of the lysosomal marker protein LAMP2 and bound antibodies to mitochondrial ATPase subunit c, indicating that the dogs suffered from a lysosomal storage disease with similarities to the neuronal ceroid lipofuscinoses. Ultrastructural analysis indicated that the storage bodies were surrounded by a single-layer membrane, but the storage granules were distinct from those reported for other lysosomal storage diseases.”
Keller et al. (2024) report histopathological findings in the affected Weimaraner: "Autofluorescent intracellular granules were observed in the cerebral and cerebellar cortexes, optic nerve, and cardiac muscle of the affected dog. These abnormal inclusions in the cerebral cortex and cardiac muscle immunolabeled with antibodies to mitochondrial ATP synthase subunit c protein, like that observed in the neuronal ceroid lipofuscinosis group of lysosomal storage diseases. Immunolabeling also demonstrated pronounced neuroinflammation in brain tissues. The ultrastructural appearances of the disease-related inclusion bodies in the brain and optic nerve were quite variable. The ultrastructure and locations of many of the inclusions in the nervous tissues suggested that they were derived, at least in part, from the myelin surrounding axons. The storage bodies in the cardiac muscle were located in mitochondria-rich regions and consisted of parallel arrays of membrane-like components interspersed with electron-dense flocculent material. The disease was characterized by pronounced abnormalities in the myelin of the brain and optic nerve consisting of distinctive areas of ballooning between the layers of myelin."

Breeds: Dalmatian (Dog) (VBO_0200427), Weimaraner (Dog) (VBO_0201401).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
CNP 2',3'-cyclic nucleotide 3' phosphodiesterase Canis lupus familiaris 9 NC_051813.1 (21614689..21606902) CNP Homologene, Ensembl , NCBI gene


By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
1502 Dalmatian (Dog) Lysosomal storage disease, CNP-related CNP deletion, small (<=20) Naturally occurring variant Dog10K_Boxer_Tasha 9 g.20350240del c.1107del p.(K370Nfs*11) ENSCAFT00000102206 2022 35447247
1680 Weimaraner (Dog) Lysosomal storage disease, CNP-related CNP missense Naturally occurring variant Dog10K_Boxer_Tasha 9 g.20355460G>A c.125C>T p.(T42M) XM_844467.6; XP_849560.2; NC_006591.4 2024 38397235

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:002591-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset].


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.

2024 Keller, S.H., Johnson, G.S., Bullock, G., Mhlanga-Mutangadura, T., Schwartz, M., Pattridge, S.G., Guo, J., Kortz, G.D., Katz, M.L. :
Homozygous CNP mutation and neurodegeneration in Weimaraners: Myelin abnormalities and accumulation of lipofuscin-like inclusions. Genes (Basel) 15:246, 2024. Pubmed reference: 38397235. DOI: 10.3390/genes15020246.
2022 Bullock, G., Johnson, G.S., Mhlanga-Mutangadura, T., Petesch, S.C., Thompson, S., Goebbels, S., Katz, M.L. :
Lysosomal storage disease associated with a CNP sequence variant in Dalmatian dogs. Gene 830:146513, 2022. Pubmed reference: 35447247. DOI: 10.1016/j.gene.2022.146513.

Edit History

  • Created by Imke Tammen2 on 15 Nov 2022
  • Changed by Imke Tammen2 on 15 Nov 2022
  • Changed by Imke Tammen2 on 08 Apr 2024