OMIA 000248-9615 : Neutropenia, cyclic in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 608233 (trait) , 603401 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2003

Cross-species summary: Also known as cyclic hematopoiesis and in humans as HERMANSKY-PUDLAK SYNDROME 2; HPS2

Species-specific name: Grey Collie Syndrome; Gray Collie Syndrome

Species-specific description: Cyclic neutropenia, also known as cyclic hematopoiesis or Grey/Gray Collie Syndrome, is characterized by cyclic fluctuations in the numbers of leucocytes, particularly neutrophils. Affected animals have an associated coat color dilution, producing a gray coat color. Affected dogs have cyclic reductions in leucocyte numbers, particularly neutrophils, which are associated with recurrent fever, anorexia, and severe infections, often life threatening. The mode of inheritance is autosomal recessive.

Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT

Mapping: CFA (3)

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Benson et al. (2003) showed that the causative mutation is a single base pair insertion in exon 20 of AP3 beta gene (AP3B1), which encodes the beta 3A subunit of adaptor protein complex 3 (AP3). This causes a frame shift in the amino acid code, and ultimately premature termination of AP3 mRNA. Affected animals are homozygous for the mutation, have no AP3 beta mRNA, while carriers have half the expected amount (Benson et al., 2003).

Clinical features: Clinical signs are associated with severe neutropenia, and include recurrent fever, anorexia, and severe infections, which can be life threatening (Dale et al., 1972, Pacheco et al., 2008). Affected animals have an associated coat color dilution, producing a gray coat color.

Pathology: AP3 is a protein complex on the cytosolic side of membrane-bound vesicles, and directs proteins from the Golgi apparatus to lysosomes. The beta subunit of AP3 recognizes neutrophil elastase (ELA2) as its cargo and transports it to lysosomal granules. In the absence of normally functioning AP3B1, ELA2 is not transported to the correct location, and does not function properly. Neutrophils of affected dogs have elastase deficiency and accumulate elastase precursor proteins in their primary granules (Meng et al., 2010).

Prevalence: The prevalence of the mutant allele in the Collie breed is unknown.

Control: Parents of affected dogs are carriers. Siblings of affected dogs should be tested for the causative mutation. It is recommended that carriers only be bred to noncarriers, in which case, testing of offspring is advisable.

Genetic testing: A test is available to detect the causative mutation.

Breed: Collie.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
AP3B1 adaptor-related protein complex 3, beta 1 subunit Canis lupus familiaris 3 NC_051807.1 (28405848..28672345) AP3B1 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 Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
580 Collie Neutropenia, cyclic AP3B1 insertion, small (<=20) Naturally occurring variant CanFam3.1 3 g.28663129_28663130insA c.2407_2408insA p.(T803Nfs*5) NM_001002974.2; NP_001002974.1; a single base pair (A) insertion in exon 20 of the AP3 beta gene (AP3B1) 2003 12897784


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.
2010 Meng, R., Bridgman, R., Toivio-Kinnucan, M., Niemeyer, GP., Vernau, W., Hock, T., Lothrop, CD. :
Neutrophil elastase-processing defect in cyclic hematopoietic dogs. Exp Hematol 38:104-15, 2010. Pubmed reference: 19941936. DOI: 10.1016/j.exphem.2009.09.010.
2008 Pacheco, J.M., Traulsen, A., Antal, T., Dingli, D. :
Cyclic neutropenia in mammals. Am J Hematol 83:920-1, 2008. Pubmed reference: 18951469. DOI: 10.1002/ajh.21295.
2004 Benson, KF., Person, RE., Li, FQ., Williams, K., Horwitz, M. :
Paradoxical homozygous expression from heterozygotes and heterozygous expression from homozygotes as a consequence of transcriptional infidelity through a polyadenine tract in the AP3B1 gene responsible for canine cyclic neutropenia. Nucleic Acids Res 32:6327-33, 2004. Pubmed reference: 15576359. DOI: 10.1093/nar/gkh974.
Horwitz, M., Benson, KF., Duan, Z., Li, FQ., Person, RE. :
Hereditary neutropenia: dogs explain human neutrophil elastase mutations. Trends Mol Med 10:163-70, 2004. Pubmed reference: 15059607. DOI: 10.1016/j.molmed.2004.02.002.
2003 Benson, K.F., Li, F.Q., Person, R.E., Albani, D., Duan, Z., Wechsler, J., Meade-White, K., Williams, K., Acland, G.M., Niemeyer, G., Lothrop, C.D., Horwitz, M. :
Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastase Nature Genetics 35:90-6, 2003. Pubmed reference: 12897784. DOI: 10.1038/ng1224.
Yanay, O., Barry, S.C., Katen, L.J., Brzezinski, M., Flint, L.Y., Christensen, J., Liggitt, D., Dale, D.C., Osborne, W.R. :
Treatment of canine cyclic neutropenia by lentivirus-mediated G-CSF delivery Blood 102:2046-52, 2003. Pubmed reference: 12750178. DOI: 10.1182/blood-2002-12-3722.
1996 Allen, W.M., Pocock, P.I., Dalton, P.M., Richards, H.E., Aitken, M.M. :
Cyclic neutropenia in Collies Veterinary Record 138:371-372, 1996. Pubmed reference: 8737267.
1995 Brabb, T., Maggioprice, L., Dale, D., Deeb, B., Liggitt, D. :
Pancreatic adenocarcinoma in two grey collie dogs with cyclic hematopoiesis Laboratory Animal Science 45:357-362, 1995. Pubmed reference: 7474871.
1991 Lothrop, C.D., Candler, R.V., Pratt, H.L., Urso, I.M., Jones, J.B., Carroll, R.C. :
Characterization of Platelet Function in Cyclic Hematopoietic Dogs Experimental Hematology 19:916-922, 1991. Pubmed reference: 1893969.
1978 Dunn, C.D.R., Jones, J.B., Jolly, J.D., Lange, R.D. :
Cell proliferation of canine cyclic hematopoietic marrow in diffusion chambers Proceedings of the Society for Experimental Biology and Medicine 158:50-53, 1978. Pubmed reference: 351627.
Yang, T.J. :
Recovery of hair coat colour in Gray Collie (cyclic neutropenia) normal bone marrow transplant chimeras American Journal of Pathology 91:149-153, 1978. Pubmed reference: 347941.
1975 Cheville, N.F. :
The Grey Collie syndrome (cyclic neutropenia) Journal of the American Animal Hospital Association 11:350-352, 1975.
1974 Adamson, J.W., Dale, D.C., Elm, R.J. :
Hematopoiesis in the Grey Collie dog : studies of the regulation of erythropoiesis Journal of Clinical Investigation 54:965-973, 1974. Pubmed reference: 4430726. DOI: 10.1172/JCI107837.
Adamson, J.W., Dale, D.C., Elm, R.J. :
Regulation of cyclic erthropoiesis in the Grey Collie Journal of Clinical Investigation 52:1A abstract, 1974.
1973 Patt, H.M., Lund, J.E., Maloney, M.A. :
Cyclic hematopoiesis in grey Collie dogs: a stem cell problem Blood 42:873-884, 1973. Pubmed reference: 4796766.
1972 Dale, D.C., Alling, D.W., Wolff, S.M. :
Cyclic hematopoiesis: the mechanism of cyclic neutropenia in Grey Collie dogs Journal of Clinical Investigation 51:2197-2204, 1972. Pubmed reference: 5054472. DOI: 10.1172/JCI107027.
1971 Reynold, H.Y., Dale, D.C., Wolff, S.M., Johnson, J.S. :
Serum immunoglobulin levels in Grey Collies Society for Experimental Biology and Medicine 136:574-577, 1971.
1970 Lund, J.E., Padgett, G.A., Gorham, J.R. :
Additional evidence on the inheritance of cyclic neutropenia in the dog Journal of Heredity 61:47-49, 1970. Pubmed reference: 5529685.
1967 Lund, J.E., Padgett, G.A., Ott, R.L. :
Cyclic neutropenia in Grey Collie dogs Blood 29:452-461, 1967. Pubmed reference: 6067150.

Edit History

  • Created by Frank Nicholas on 20 Nov 2010
  • Changed by Martha MaloneyHuss on 18 Aug 2011
  • Changed by Vicki Meyers-Wallen on 10 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 21 Sep 2012
  • Changed by Frank Nicholas on 26 Jan 2013