Keith C. Barnett

Mutation in HSF4 is associated with hereditary cataract in the Australian Shepherd.

Cataracts are a leading cause of blindness in dogs with approximately 100 breeds affected by primary hereditary forms. Despite the large number of breeds affected with hereditary cataracts (HC) little is known about the genetics of the condition, and to date only a single gene, HSF4, has been implicated in the development of the disease in dogs. We previously identified a recessively inherited 1-bp insertion in the transcription factor gene HSF4 resulting in the loss of the open reading frame in Boston terriers and Staffordshire bull terriers. While testing the insertion mutation in other breeds with HC, we identified a 1-bp deletion at the same nucleotide of HSF4 in some Australian Shepherds with cataract. Using DNA samples from almost 400 privately owned Australian Shepherds we have investigated the association between the deletion mutation in HSF4 and cataracts in this breed. We conclude that the mutation is significantly associated with cataracts and that a dog carrying the mutation is approximately 17 times more likely to develop binocular cataracts than dogs that are clear of the mutation. The data also indicate that additional mutations associated with the development of cataracts are likely to be co-segregating in the Australian Shepherd population.

Ophthalmic and cone derived electrodiagnostic findings in outbred Miniature Long-haired Dachshunds homozygous for a RPGRIP1 mutation

OBJECTIVE To investigate ophthalmic and cone-derived electrodiagnostic findings in outbred Miniature Long-haired Dachshunds (MLHD) homozygous for a mutation in the RPGRIP1 gene previously associated with cone-rod dystrophy 1 (cord1). ANIMALS A total of 36 MLHD homozygous for the RPGRIP1 mutation and 23 dogs clear of the mutation (control group). PROCEDURES The dogs underwent ophthalmic examination and photopic electroretinogram (ERG) recordings. RESULTS None of the control dogs presented with clinical or ophthalmic signs consistent with cord1. Amongst the dogs homozygous for the mutation one presented with bilateral symmetrical total retinal atrophy. None of the other dogs in this group showed signs consistent with cord1. Photopic ERG recordings were available in 23 control dogs and 34 dogs homozygous for the mutation. Photopic a- and b-waves following four light stimuli (3 cdS/m(2) ) at a rate of 5.1 Hz were not significantly different between groups. The amplitudes of the 30 Hz flicker (128 flashes, 3 cdS/m(2) ) response were significantly reduced in the dogs homozygous for the PRGRIP1 mutation. The difference in age between the two groups did not significantly affect the difference. CONCLUSION Homozygosity of the RPGRIP1 mutation does not invariably result in early onset cord1. However, cone derived ERG recordings show evidence of a reduced cone or inner retinal function in homozygous but clinically normal MLHD. Modifying genes that have yet to be identified may influence an individual dogs risk of developing the blinding cord1 and also the age of onset and rate of progression.

Congenital keratoconjunctivitis sicca and ichthyosiform dermatosis in 25 Cavalier King Charles spaniel dogs – part I: clinical signs, histopathology, and inheritance

The clinical presentation and progression (over 9 months to 13 years) of congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID) in the Cavalier King Charles spaniel dog are described for six new cases and six previously described cases. Cases presented with a congenitally abnormal (rough/curly) coat and signs of KCS from eyelid opening. Persistent scale along the dorsal spine and flanks with a harsh frizzy and alopecic coat was evident in the first few months of life. Ventral abdominal skin was hyperpigmented and hyperkeratinized in adulthood. Footpads were hyperkeratinized from young adulthood with nail growth abnormalities and intermittent sloughing. Long-term follow-up of cases (13/25) is described. Immunomodulatory/lacrimostimulant treatment had no statistically significant effect on Schirmer tear test results, although subjectively, this treatment reduced progression of the keratitis. Histopathological analysis of samples (skin/footpads/lacrimal glands/salivary glands) for three new cases was consistent with an ichthyosiform dermatosis, with no pathology of the salivary or lacrimal glands identified histologically. Pedigree analysis suggests the syndrome is inherited by an autosomal recessive mode.

Congenital keratoconjunctivitis sicca and ichthyosiform dermatosis in Cavalier King Charles spaniel dogs. Part II: candidate gene study.

PURPOSE To identify causative mutation(s) for congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID) in Cavalier King Charles spaniel (CKCS) dogs using a candidate gene approach. METHODS DNA samples from 21 cases/parents were collected. Canine candidate genes (CCGs) for similar inherited human diseases were chosen. Twenty-eight candidate genes were identified by searching the Pubmed OMIM database (http://www.ncbi.nlm.nih.gov/omim). Canine orthologues of human candidate genes were identified using the Ensembl orthologue prediction facility (http://www.ensembl.org/index.html). Two microsatellites flanking each candidate gene were selected, and primers to amplify each microsatellite were designed using the Whitehead Institute primer design website (http://frodo.wi.mit.edu/primer3/). The microsatellites associated with all 28 CCGs were genotyped on a panel of 21 DNA samples from CKCS dogs (13 affected and eight carriers). Genotyping data was analyzed to identify markers homozygous in affected dogs and heterozygous in carriers (homozygosity mapping). RESULTS None of the microsatellites associated with 25 of the CCGs displayed an association with CKCSID in the 21 DNA samples tested. Three CCGs associated microsatellites were monomorphic across all samples tested. CONCLUSIONS Twenty-five CCGs were excluded as cause of CKCSID. Three CCGs could not be excluded from involvement in the inheritance of CKCSID.

Contralateral optic neuropathy and retinopathy associated with visual and afferent pupillomotor dysfunction following enucleation in six cats

PURPOSE To investigate contralateral optic neuropathy and retinopathy following enucleation in 6 cats. METHODS Retrospective study. The medical records of cats with contralateral visual and afferent pupillomotor dysfunction following enucleation presented to the Animal Health Trust (AHT), Newmarket, UK, between January 1994 and January 2010 were reviewed. Information recorded included history, signalment, ophthalmic findings, electroretinography (ERG) (2/6) and MRI (3/6) findings and long-term outcome. Pearsons chi-square tests were used to compare breed proportions (P < 0.05). RESULTS Six cats aged 1.5 to 11 (median 5.5) years presented with mydriasis and/or visual deficits noted immediately following enucleation. Enucleation involved optic nerve (ON) ligation in all of the four cases for which this information was available. Ophthalmic findings included mydriasis with absent pupillary light reflex (PLR) (4/6), incomplete PLRs (2/6), absence of dazzle reflex (4/6) and absence of menace response (4/6). Funduscopy initially revealed multifocal peripapillary retinal lesions, with subsequent progressive optic nerve head (ONH) and retinal atrophy. ERG recordings revealed normal outer retinal function at 6 and 22 weeks (2/2). On MRI, the optic chiasm (OC) ipsilateral to the enucleation could not be identified and the contralateral OC was atrophied (3/3). CONCLUSIONS The acute afferent ON deficits following enucleation, progressive ONH atrophy, normal outer retinal function and MRI demonstrating OC pathology are consistent with chiasmal injury due to traction on the ON during enucleation. Rostral traction on the globe to facilitate ON ligation is contraindicated in cats.