Hereditary deafness and mast cell tumors in dogs: Sequence analysis of candidate genes from the melanocyte development pathway

The dog is the result of centuries of breeding by humans. Various genetic diseases are prevalent in various breeds of dog as compared to mixed bred dogs. One example is a hereditary sensorineural deafness that is often accompanied by abnormal pigmentation, seen primarily in breeds with merle or white spotting coat patterns. Examination of deaf dogs has revealed an absence of melanocytes in the cochleas of affected ears. Among other functions, melanocytes produce the pigment melanin, which determines coat color. Similar conditions of hearing loss and pigmentation in other species are linked to mutations in genes from the melanocyte development pathway. Mutations in these genes also cause other diseases besides hearing loss and pigmentation. The purpose of this study was to examine selected members of this set of genes at the molecular level in the dog and evaluate their potential role in hereditary deafness and selected other conditions. Candidate genes were selected based on similarity of the phenotype seen in other species to that in the dog. The genes for endothelin receptor B (EDNRB), microphthalmia-associated transcription factor (MITF), KIT and its ligand ( KITLG) were examined by sequencing the entire coding region in I normal and 7 deaf dogs. No causative mutations were found during the course of the sequencing, however other features such as alternative splicing events, single nucleotide polymorphisms (SNPs), a microsatellite, and a pseudogene were identified. SNPs in KIT and EDNRB were not found to be associated with deafness in the Jack Russell Terrier. It appears unlikely that any of the candidate genes are responsible for deafness in dogs. In addition to deafness, the KIT gene was examined for its involvement in mast cell tumors. Examination of 88 tumors revealed duplications and deletions that appeared to be associated with tumors of higher grade. Duplications similar to those in this study result in constitutive activation of KIT. Other activating mutations of KIT have been shown to result in tumor formation. Further study is needed to determine the exact nature of its involvement, including the effect of drugs targeting such activation on the biological behavior of these tumors.