Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 608233 (trait) , 603401 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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. Lee et al. (2022) reported a mixed-breed puppy with the same clinical signs of this disorder as seen in Collies, and which was homozygous for the likely causal insertion variant reported in Collies (OMIA variant 580). However, the authors reported that "The puppy does not have phenotypic features suggestive of a collie and is presumed to be a cross between a Labrador Retriever and a Mastiff". Consequently, they concluded that "the AP3B1 mutation and CH are present within the general canine population and are not restricted to collies".

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.

Breeds: Basset Hound (Dog) (VBO_0200126), Collie (Dog) (VBO_0200375), Mixed Breed (Dog) (VBO_0200902).
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: