Help us fight disease and injury in animals

Canine genetics success stories

Primary Lens Luxation

Primary Lens Luxation (PLL) is a well-recognised, painful and blinding inherited eye condition that affects many breeds of dog, particularly Terrier and Terrier-type breeds including (but not restricted to) Miniature Bull Terriers, Tibetan Terriers, Jack and Parson Russell Terriers, Lancashire Heelers and Chinese Crested dogs.  In affected dogs the zonular fibres that support the lens break down or disintegrate, causing the lens to fall into the wrong position within the eye.  If the lens falls into the anterior chamber of the eye, glaucoma and loss of vision can quickly result.

In 2009 the Canine Genetics team at the AHT, in collaboration with Dr David Sargan (University of Cambridge, UK), Dr David Gould (Davies Veterinary Specialists, UK) and Gary Johnson’s team at the University of Missouri, USA, identified a mutation that is responsible for the development of PLL in many different breeds of dog.  The AHT now offers a DNA test for PLL that examines the DNA from each dog being tested for the presence or absence of this precise mutation. 

References

An ADAMTS17 Splice Donor Site Mutation in Dogs with Primary Lens Luxation
Farias FH, Johnson GS, Taylor JF, Giuliano E, Katz ML, Sanders DN, Schnabel RD, McKay SD, Khan S, Gharahkhani P, O'Leary CA, Pettitt L, Forman OP, Boursnell M, McLaughlin B, Ahonen S, Lohi H, Hernandez-Merino E, Gould DJ, Sargan D, Mellersh CS
Investigative Ophthalmology and Visual Science 2010 51: 4716-4721

ADAMTS17 Mutation Associated With Primary Lens Luxation Is Widespread Among Breeds
Gould D, Pettitt L, McLaughlin B,Holmes N, Forman O,  Thomas A,  Ahonen S,  Lohi H, O'Leary C,  Sargan D, Mellersh C
Veterinary Ophthalmology, in press

 

Hereditary Cataract

Cataracts are a leading cause of blindness in dogs.  Using a candidate gene approach, scientists in the Canine Genetics team at the AHT have successfully identified the mutation that causes both hereditary cataract (HC) in Staffordshire Bull Terriers and early onset hereditary cataract (EHC) in Boston Terriers.  This is the first mutation to be associated with HC in dogs and is an important breakthrough from both genetics and breeding viewpoints. A DNA test, exclusive to the AHT, is now being offered which will determine the genetic status of dogs, with respect to this mutation, and inform breeders which dogs can be mated together safely, without the risk of producing affected puppies.  Further investigation of the discovered HC causal mutation highlighted a dominant variant in the same gene which conclusively proved to be an increased risk factor for the development of cataract in the Australian Shepherd.  A DNA test is also available for this breed.

References

 

Identification of mutations in HSF4 in dogs of three different breeds with hereditary cataracts
Mellersh CS, Pettitt L, Forman OP, Vaudin M, Barnett KC
Veterinary Ophthalmology 2006 9: 369-378

Mutation in HSF4 associated with early but not late-onset hereditary cataract in the Boston Terrier
Mellersh CS, Graves KT, McLaughlin B, Ennis RB, Pettitt L, Vaudin M, Barnett KC
Journal of Heredity 2007 98: 531-533

Mutation in HSF4 is associated with hereditary cataract in the Australian Shepherd
Mellersh CS, McLaughlin B, Ahonen S, Pettitt L, Lohi H, Barnett KC
Veterinary Ophthalmology 2009 12: 372-378

 

L-2-hydroxyglutaric aciduria

L-2-hydroxyglutaric aciduria (L-2-HGA) is a devastating disease that affects the nervous system.  Clinical symptoms appear between the ages of six months and one year of age, and include seizures, incoordination (ataxia or wobbly gait), tremors and altered behaviour.  Towards the end of 2004, two scientific papers were published announcing the identification of the gene involved with L-2-HGA in humans.  We sequenced the same gene in affected and unaffected dogs and identified the mutation causing L-2-HGA in Staffordshire Bull Terriers.  A DNA test for L-2-HGA is currently being offered at the AHT to diagnose L-2-HGA in Staffordshire Bull Terriers.

References

L-2-hydroxyglutaric aciduria: characterisation of the molecular defect in a spontaneous canine model
Penderis J, Calvin J, Abramson C, Jakobs C, Pettitt L, Binns MM, Verhoeven NM, O'Driscoll E, Platt SR, Mellersh CS
Journal of Medical Genetics 2007 44: 334-340

 

Progressive retinal atrophy

Progressive retinal atrophy (PRA) is an inherited degenerative disease of the retina; various forms of which affect many breeds of dog. 

Prcd-PRA has been found in a small number of Golden Retrievers (GR) in the US, but it does not account for all cases of PRA in this breed in the US nor the majority in Europe.

Genetic analysis of dogs from the UK and Sweden enabled the AHT, in collaboration with the University of Agricultural Sciences in Uppsala, Sweden, to identify an additional mutation that accounts for approximately 65% of PRA cases in the Golden Retriever (Downs et al, manuscript in press).  A DNA test for this mutation was launched at the AHT on 15th November 2010.

Genetic analysis of both a large inbred pedigree and outbred dogs from the worldwide pet population enabled the AHT to identify a mutation that is associated with PRA in Miniature Long-Haired Dachshunds.  A DNA test for this mutation is currently being offered at the AHT.  We have also found the identical mutation present in English Springer Spaniels and, in collaboration with Dr Gary Johnson at the University of Missouri, USA, we have confirmed that dogs that carry two copies of the mutation have a significantly increased risk of developing PRA.  A DNA test for PRA in the English Springer Spaniel was launched in April 2007.

In collaboration with Claudia Busse (Ophthalmology, AHT) and Dr David Sargan and Keiko Miyadera (University of Cambridge, UK), we are continuing to investigate the genetic basis of PRA in the Miniature Long-Haired Dachshund, and in particular why there is considerable variation in the age at which Miniature Long-Haired Dachshunds that carry two copies of the PRA mutation develop clinical disease.

The first dog in which PRA was ever described was a Gordon Setter in 1909.  More recently a number of Gordon Setters have developed PRA very late in life, at about 10 years of age.  In collaboration with Tufts University, the Canine Genetics team at the AHT analysed the DNA of Gordon Setters from the US and UK and identified the mutation thought to cause late-onset PRA in the breed.  The mutation accounts for 95% of PRA cases in the Gordon Setter (manuscript in preparation).  A DNA test for this mutation was launched at the AHT on 14th March 2011.

References

Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis
Mellersh CS, Boursnell ME, Pettitt L, Ryder EJ, Holmes NG, Grafham D, Forman OP, Sampson J, Barnett KC, Blanton S, Binns MM, Vaudin M
Genomics 2006 88: 293-301

Phenotypic variation and genotype-phenotype discordance in canine cone-rod dystrophy with an RPGRIP1 mutation
Miyadera K, Kato K, Aguirre-Hernández J, Tokuriki T, Morimoto K, Busse C, Barnett K, Holmes N, Ogawa H, Sasaki N, Mellersh CS, Sargan DR
Molecular Vision 2009 15: 2287-2305

Ophthalmic and cone derived electrodiagnostic findings in outbred Miniature Long-haired Dachshunds homozygous for a RPGRIP1 mutation
Busse C, Barnett KC, Mellersh CS, Adams VJ
Veterinary Ophthalmology 2011 14: 146-152

A Frameshift Mutation in Golden Retriever Dogs with Progressive Retinal Atrophy Endorses SLC4A3 as a Candidate Gene for Human Retinal Degenerations
Downs LM, Wallin-Håkansson B, Boursnell M, Marklund S, Hedhammer A, Truvé K, Hübinette L, Lindblad-Toh K, Bergström T, Mellersh CS
PLoS ONE2011;6:e21452.

 

Copper toxicosis

Copper toxicosis in Bedlington Terriers is a genetic disorder causing elevated liver copper levels.  Affected dogs suffer from hepatitis and progressive cirrhosis of the liver.  The gene causing this disorder had been discovered previously, and a large deletion was shown to be the causal mutation for the disease.  Additional work at the AHT has enabled the mutation to be fully characterised, allowing development of a robust DNA test.

 

 

 

 

References

Identification of a new copper metabolism gene by positional cloning in a purebred dog population.
van De Sluis B, Rothuizen J, Pearson PL, van Oost BA, Wijmenga C
Human Molecular Genetics 2002 11:165-173

Characterization of the COMMD1 (MURR1) mutation causing copper toxicosis in Bedlington terriers
Forman OP, Boursnell ME, Dunmore BJ, Stendall N, van den Sluis B, Fretwell N, Jones C, Wijmenga C, Rothuizen J, van Oost BA, Holmes NG, Binns MM, Jones P
Animal Genetics 2005 36: 497-501

 

Episodic Falling and Dry Eye Curly Coat Syndrome

Episodic Falling (EF) in the Cavalier King Charles Spaniel (CKCS) is a serious, debilitating, inherited condition that is distressing for both affected dogs and their owners.  EF is an inherited 'exercise-induced hypertonicity disorder' meaning that there is increased muscle tone and the muscles are unable to relax.  Episodes usually occur in response to excitement, exercise, or frustration, except in severe cases in which symptoms may be chronic or happen with no apparent cause.  Clinical signs usually appear before one year of age and both male and female dogs are affected.

Dry Eye Curly Coat Syndrome, known clinically as Congenital Keratoconjunctivitis Sicca and Ichthyosiform Dermatosis, affects a dog’s eyes and skin.  Affected dogs produce no tears making their eyes incredibly sore.  Their skin becomes very flaky and dry, particularly around the foot, and this can make standing and walking difficult and painful.  This syndrome appears to be a problem unique to CKCS and most dogs diagnosed with the condition are put to sleep.
 
With funding from the Waltham foundation (Pedigree Masterfoods) and the Kennel Club Charitable Trust we have identified mutations associated with both of these conditions, and DNA tests are now available.  Further research is now underway to calculate the frequency of the two mutations in the CKCS population in the UK and other countries.  For more information please contact Lou Hayward