In other species: killer whale , taurine cattle , American mink , Arctic fox

Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 214500 (trait) , 606897 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0008963: Chediak-Higashi syndrome

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2020

Cross-species summary: The mouse homologue of this disorder is the beige coat-colour mutation, which is a mutation in the gene for lysosomal trafficking regulator, Lyst. As its name suggests, this gene is involved in lysosomal functioning - lysosomes being the digestive system of the cell. Thus Chediak-Higashi syndrome is a lysosomal disorder.

Species-specific symbol: CHS

Species-specific description: Cats with Chediak-Higashi syndrome (CHS) have a very characteristic smoke-blue coat and yellow eyes, with concurrent bleeding disorders and impaired vision. The first report of this disorder in cats was by Krammer et al. (1975, 1977), and two research colonies were created. As summarised by Buckley et al. (2020), "after nearly 20 years of research, the colonies at Colorado State and Washington State University could no longer be maintained and were lost to the research community. Fortunately, during the dissolution of the former CHS colony, an intact male (Smokey) was donated to the University of California, Davis. Smokey, a 16-year-old carrier for CHS, represented the only viable representative of the cat biomedical model for CHS. Therefore, the feline model for CHS provided an opportunity to apply newly advanced assisted reproductive techniques to resurrect a previously extinct feline disease model". This technology was utilised by Buckley et al. (2020), with the result that "semen from the viable CHS carrier of the original CHS colony, was successfully cryopreserved and used for artificial insemination (AI) to produce potential CHS carrier offspring."

Molecular basis: By whole-genome sequencing fibroblast cell lines that had been maintained from one of the original colony affected cats, Buckley et al. (2020) " identified a candidate causal variant as a ~20 kb tandem duplication within LYST, spanning exons 30 through to 38 (NM_001290242.1:c.8347-2422_9548 + 1749dup). PCR genotyping of the produced offspring demonstrated three individuals inherited the mutant allele from the CHS carrier male."

Clinical features: Cats with CHS develop oculocutaneous albinism, resulting in smoke-blue coat colour and yellow eyes and ocular abnormalities such as photophobia, cataracts (Krammer et al., 1977) and rotatory nystagmus (Collier et al., 1979). They also develop bleeding diathesis, commonly presented as easy bruising, epistaxis, gingival bleeding, prolonged bleeding, and in severe cases, life-threatening haemorrhages (Cowles et al., 1992). Auditory brainstem response test shows abnormalities in the brainstem auditory pathway although its implications on the cats’ hearing is unknown (Creel et al., 1994). CHS cats are also more prone to bacterial infections (Prieur et al., 1981) due to their impaired immune system. [IT thanks DVM student Michelle Kim, who provided the basis of this contribution in April 2022.]

Pathology: Histopathological examination of skin, hair and eyes showed clumping of melanin granules which was the basis of partial albinism (Prieur and Collier, 1978). Microscopic examination revealed granular clumping and enlargement of polymorphic leukocytes, resulting in defective chemotactic and phagocytic capabilities (due to the delayed delivery of lysosomal contents (Prieur and Collier, 1978). Platelet abnormalities were associated with the absence secretable serotonin, ADP and granules leading to bleeding diathesis (Cowles et al., 1992). Ultrastructural examination of retinal pigmented epithelium showed abnormalities in melanosomes and pre-melanosomes associated with tapetal degeneration and altered retinal fibre projections to the lateral geniculate body (Creel et al., 1982). [IT thanks DVM student Michelle Kim, who provided the basis of this contribution in April 2022.]

Breed: Persian (Cat) (VBO_0100188).
Breeds in which the phene or likely causal variants have been documented. If a likely causal variant has been documented, see variant-specific breed information in the variant table. (Breed information may be incomplete).

Associated gene: