UC Davis School of Veterinary Medicine Veterinary Genetics Laboratory

French Bulldog Health Panel

Tests Offered:
CDDY & CDPA | CMR1 |DM |HUU | JHC

Chondrodystrophy (CDDY and IVDD Risk) and Chondrodysplasia (CDPA)

Introduction

Chondrodysdrophy (CDDY) is a trait that defines many dog breeds and is characterized by reduction of long bone length (shorter legs) as a consequence of early changes in the structure of growth plates. CDDY can also impact health of animals through an abnormal process that causes premature degeneration of the intervertebral discs. Two retrogene insertions of functional fibroblast growth factor 4 (FGF4) explain short-legged phenotypes of dogs. FGF4 gene is involved in many biological processes including bone development.

The first insertion discovered (Parker et al 2009) is an FGF4-retrogene insertion in dog chromosome 18 (FGF4-18). This FGF4-18 insertion explains a short-legged phenotype known as chondrodysplasia (CDPA) in breeds such as Basset Hound, Pembroke Welsh Corgi, Dachshunds, West Highland White Terriers and Scottish Terriers. CDPA inheritance is considered to follow am autosomal dominant mode.

The Chondrodysdrophy (CDDY) mutation was recently discovered by researchers in the Bannasch Laboratory at the University of California, Davis (Brown et al. 2017) as a second FGF4-retrogene insertion in dog chromosome 12.  CDDY includes a short-legged phenotype and abnormal premature degeneration of intervertebral discs leading to susceptibility to Hansen’s type I intervertebral disc disease (IVDD). The intervertebral disc, which sits between vertebrae, is composed of an outer fibrous basket (annulus fibrosus) made of 70% collagen and an inner gel-like layer called the nucleus pulposus. These structures allow for flexibility of the vertebral column. In Chondrodystrophic breeds, premature calcification of the nucleus pulposus at early age (from birth to 1 year of age) results in degeneration of all discs in young dogs. These abnormal discs are predisposed to herniation into the spinal canal where the inflammation, and hemorrhage can cause severe pain and neurological dysfunction (myelopathy) termed Intervertebral Disc Disease or IVDD. IVDD has high mortality rate and high cost of surgical and medical veterinary care.

CDDY is inherited as a semi-dominant trait for height, meaning that dogs with 2 copies of the mutation are smaller than dogs with only 1 copy. With respect to IVDD, the inheritance follows a dominant mode, meaning that 1 copy of the FGF4-12 mutation is sufficient to predispose dogs to IVDD. Dogs that have both FGF4-12 and FGF4-18 show a more drastic reduction of leg length.  One area of current investigation is how CDDY and CDPA might work in concert to increase the risk of IVDD.

The Veterinary Genetics Laboratory offers a combined test for CDDY and CDPA for breeds that have long and short leg phenotypes. CDDY and CDPA occur in many breeds. Testing for these mutations can help breeders determine if CDDY is present among breeding stock and to identify dogs at risk for IVDD. In breeds where both mutations are present, breeders can benefit from test results to implement breeding strategies to reduce incidence of CDDY, while retaining the short-legged phenotype conferred by CDPA.

CDDY variant has been found in breeds such as: Basset Hound, Beagle, Bichon Frise, Cardigan Welsh Corgi, Cavalier King Charles Spaniel, Chesapeake Bay Retriever, Chihuahua, American Cocker Spaniel, Coton de Tulear, Dachshund, Dandie Dinmont Terrier, English Springer Spaniel, French Bulldog, Havanese, Jack Russell Terrier, Nova Scotia Duck Tolling Retriever, Pekingese, Pembroke Welsh Corgi, Poodle (Miniature and Toy), Portuguese Water Dog, Scottish Terrier, Shih Tzu. This is not a complete list of breeds. Research on the distribution of this mutation across breeds is ongoing.

ORDER TEST KITS | PRICE LIST
Allow 5-10 business days for results.

Results reported as:

Chondrodystophy (CDDY and IVDD Risk)

N/N No copies of CDDY mutation.
N/CDDY 1 copy of CDDY mutation. Dog is short-legged and at risk for IVDD.
CDDY/CDDY 2 copies of CDDY. Dog is short-legged and at risk for IVDD.

Chondrodysplasia

N/N No copies of CDPA mutation.
N/CDPA 1 copy of CDPA. Dog is short-legged.
CDPA/CDPA 2 copies of CDPA. Dog is short-legged.

References:

Parker HG, VonHoldt BM, Quignon P, Margulies EH, Shao S, Mosher DS, Spady TC, Elkahloun A, Cargill M, Jones PG, Maslen CL, Acland GM, Sutter NB, Kuroki K, Bustamante CD, Wayne RK, Ostrander EA. 2009. An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science 325(5943):995-8. doi: 10.1126/science.1173275.

Brown EA, Dickinson PJ, Mansour T, Sturges BK, Aguilar M, Young AE, Korff C, Lind J, Ettinger CL, Varon S, Pollard R, Brown CT, Raudsepp T, & Bannasch DL. (2017) FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs.
PNAS 114 (43) 11476-11481.
http://m.pnas.org/content/early/2017/10/09/1709082114.

Canine Multifocal Retinopathy 1

Introduction

Canine Multifocal Retinopathy 1 (CMR1) is an inherited eye disease caused by a mutation (c.73C>T) in the Bestrophin 1 gene that results in a shortened, dysfunctional protein. Affected dogs typically present with multiple, discrete circular areas of retinal detachment between 11 and 16 weeks of age. Fluid accumulates under the detached retina resulting in gray, tan, orange or pink “blisters” in the eye. Progression of retinal changes is slow, ceases by 1 year and does not lead to blindness. In some cases, the blisters appear to heal as the dog ages but vision loss has been reported. The disease is inherited in an autosomal recessive fashion thus two copies of the CMR1 mutation must be present to produce the disease. Breeding two carriers is predicted to produce 25% affected pups

The VGL offers a genetic test for the CMR1 mutation. Genetic screening helps breeders establish the genetic status of breeding stock and select mating pairs appropriately in order to reduce the risk of producing CMR1-affected offspring.

Testing is recommended for: American Bulldog, American Bully, Aussiedoodle, Australian Koolie, Australian Shepherd, Brazilian Terrier, Bulldog, Bullmastiff, Cane Corso, Dogue de Bordeaux, French Bulldog, Great Pyrenees, Havanese, Koolie, Mastiff, Miniature American Shepherd, Miniature Australian Shepherd, Perro de Presa Canario, Shorty Bull, South African Boerboel, Toy Australian Shepherd

ORDER TEST KITS | PRICE LIST
Allow 5-10 business days for results.

Results reported as:

N/N Normal - no copies of the CMR1 mutation
N/CMR1 Carrier - 1 copy of the CMR1 mutation; dog is normal
CMR1/CMR1 Affected - 2 copies of the CMR1 mutation; dog will develop multifocal retinopathy

Reference:

Gornik KR, Pirie CG, Duker JS, Boudrieau RJ. Canine multifocal retinopathy caused by a BEST1 mutation in a Boerboel. Vet Ophthalmol. 2013 Sep 3. [PubMed: 23998685]

Donner J, Kaukonen M, Anderson H, Moller F, Kyostila K, Sankari S, Hytonen M, Giger U, Lohi H. Genetic Panel Screening of Nearly 100 Mutations Reveals New Insights into the Breed Distribution of Risk Variants for Canine Hereditary Disorders. PLoS One. 2016 Aug 15;11(8). [PubMed: 27525650]

Degenerative Myelopathy

Introduction

Degenerative myelopathy (DM) is an inherited neurologic disorder of dogs similar to Lou Gehrig’s disease in humans and results from a mutation (c.118G>A) in the SOD1 gene. Affected dogs usually present clinical signs of disease in adulthood (at least 8 years of age) with gradual muscle wasting and loss of coordination that typically begins in the hind limbs because of nerve degeneration. Disease progression continues until the dog is unable to walk. Small breed dogs tend to progress more slowly. In late stages of the disease, dogs may become incontinent and the forelimbs may be affected. Affected dogs may fully lose the ability to walk 6 months to 2 years after the onset of signs. The disease is inherited in an autosomal recessive fashion with incomplete penetrance. Thus, two copies of the SOD1 mutation (DM/DM) confer increased risk for DM but not all DM/DM dogs across breeds will develop the disease. The variable presentation between breeds suggests that other genetic and environmental factors play a role in disease expression. There is ongoing research to identify other genetic factors that modify risk for DM in different breeds. In addition, similar disease presentation is observed in some animals lacking the SOD1 mutation. Breeding two carriers of the SOD1 mutation together is predicted to produce 25% pups that may develop DM.

The VGL offers a genetic test for the SOD1 c.118G>A mutation. Genetic screening helps breeders establish the genetic status of breeding stock and select mating pairs appropriately to reduce the risk of producing DM-affected offspring.

Testing is recommended for: many breeds

The Degenerative Myelopathy (DM) test is a patented test outside of the United States. The Veterinary Genetics Laboratory is not authorized to offer the DM test outside of the United States at this time.

ORDER TEST KITS | PRICE LIST
Allow 5-10 business days for results.

Results reported as:

N/N No copies of the DM mutation
N/DM 1 copy of the DM mutation
DM/DM 2 copies of the DM mutation; dog may develop DM disease

References:

Awano T, Johnson GS, Wade CM, Katz ML, Johnson GC, Taylor JF, Perloski M, Biagi T, Baranowska I, Long S, March PA, Olby NJ, Shelton GD, Khan S, O'Brien DP, Lindblad-Toh K, Coates JR. Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2009 Feb 24; 106(8):2794-9. [PubMed: 19188595]

Coates JR, March PA, Oglesbee M, Ruaux CG, Olby NJ, Berghaus RD, O'Brien DP, Keating JH, Johnson GS, Williams DA. Clinical characterization of a familial degenerative myelopathy in Pembroke Welsh Corgi dogs. J Vet Intern Med. 2007 Nov-Dec; 21(6):1323-31. [PubMed: 18196743]

Shelton GD, Johnson GC, O’Brien DP, Katz ML, Pesayco JP, Chang BJ, Mizisin AP, Coates JR. Degenerative myelopathy associated with a missense mutation in the superoxide dismutase 1 (SOD1) gene progresses to peripheral neuropathy in Pembroke Welsh Corgis and Boxers. J Neurol Sci. 2012 Jul 15;318(1-2):55-64. [PubMed: 22542607]

Zeng R, Coates JR, Johnson GC, Hansen L, Awano T, Kolicheski A, Ivansson E, Perloski M, Lindblad-Toh K, O'Brien DP, Guo J, Katz ML, Johnson GS. Breed Distribution of SOD1 Alleles Previously Associated with Canine Degenerative Myelopathy. J Vet Intern Med. 2014, 28(2):515-521.

Canine Hyperuricosuria
Introduction

Hyperuricosuria (HUU) means elevated levels of uric acid in the urine. This trait predisposes dogs to form stones in their bladders or sometimes kidneys. These stones often must be removed surgically and can be difficult to treat. HUU is inherited as a simple autosomal recessive defect. A mutation in exon 5 of the gene Solute carrier family 2, member 9 (SLC2A9) has been found to be associated with hyperuricosuria in dogs. HUU can occur in any breed but is most commonly found in the Dalmatian, Bulldog and Black Russian Terrier. While traditional Dalmatians are homozygous for HUU (HU/HU), the introduction of “low uric acid” dogs, derived from Dalmatian x Pointer backcrosses, into the purebred gene pool has provided a means for breeders to reduce incidence of the disease and maintain the breed characteristics. Normal (N/N) and carrier (N/HU) Dalmatians are now present in the breed, and trace to the backcross lineage.

A DNA test for the SLC2A9 mutation can determine the genetic status of dogs for HUU. Dogs that carry two copies of the mutation will be affected and susceptible to develop bladder/kidney stones. The SCL2A9 mutation is not the sole cause of urate bladder stones in dogs. Other factors such as liver disease and diet need also be considered in clinical evaluation.

ORDER TEST KITS | PRICE LIST
Allow 3-6 business days for results.

Detailed Hyperuricosuria Information

The VGL offers a DNA test for hyperuricosuria to assist owners and breeders in identifying affected and carrier dogs. The test uses DNA collected from buccal swabs thus avoiding invasive blood collection. Breeders can use results from the test as a tool for selection of mating pairs to avoid producing affected dogs. The test is offered to all breeds, including American Pitbull Terrier, American Staffordshire Terrier, Australian Shepherd, Black Russian Terrier, Bulldog, Catahoula Leopard Dog, Dalmatian, Danish-Swedish Farmdog, German Hunting Terrier, German Shepherd, Giant Schnauzer, Jack Russel/Parsons Terrier, Kromfohrländer, Labrador Retriever, Lagotto Romagnolo, Large Munsterlander, South African Boerboel, Spaniel de Pont-Audemer, Swedish Vallhund, Vizsla and Weimaraner.

Results reported as:

N/N No copies of hyperuricosuria mutation; dog is normal
N/HU 1 copy of hyperurisosuria mutation; dog is normal but is a carrier
HU/HU 2 copies of hyperuricosuria mutation; dog is affected and susceptible to develop bladder/kidney stones.

Research Hyperuricosuria is ongoing to determine other breeds with this problem.  We recommend testing any dog that has formed kidney or bladder stones composed of urate or uric acid. If the dog has the mutation then treatment modalities for Dalmatians can be used to treat the dog.

References:

Bannasch D, N Safra, A Young, N Karmi, RS Schaible and GV Ling (2008) Mutations in the SLC2A9 Gene Cause Hyperuricosuria and Hyperuricemia in the Dog. PLoS Genetics 4(11): e1000246. doi:10.1371/journal.pgen.1000246

Karmi N, EA Brown, SS Hughes, B McLaughlin, CS Mellersh, V Biourge, and DL Bannasch (2010) Estimated Frequency of the Canine Hyperuricosuria Mutation in Different Dog Breeds. Journal of Veterinary and Internal Medicine 2010;24:1337–1342.

Juvenile Hereditary Cataracts

Cataracts are a common cause of blindness in dogs. Cataracts are defined as the clouding (opacity) of the lens of the eye. The lens focuses light on the retina to enable vision. Cataracts can therefore impair vision and, if progressive, they can lead to total blindness.  Cataracts can develop in one eye (unilateral) or both (bilateral) as a result of the normal aging process, underlying diseases, injury, or be caused by a genetic defect (primary hereditary cataracts). Primary hereditary cataracts tend to be of the bilateral type. In dogs, mutations in the HSF4 gene are associated with two different forms of cataracts, Juvenile Hereditary Cataract (JHC) and Hereditary Cataract (HC).

Juvenile Hereditary Cataract (JHC) found in Boston Terriers, Staffordshire Bull Terriers, and French Bulldogs is a recessive disorder (2 copies of the mutation are necessary for cataracts to develop). JHC affects both eyes symmetrically and has early onset, with cataract formation starting before 1 year of age and progressing to maturity and blindness by 2-3 years of age. JHC affects both sexes equally. Mating of two carriers (N/JHC x N/JHC) is predicted to produce 25% of affected pups. JHC is distinct from the late-onset hereditary cataract also found in Boston Terriers and other breeds, the cause of which has not yet been identified.

Testing recommendation:

Juvenile Hereditary Cataracts (JHC): Boston Terriers, French Bulldogs, Staffordshire Bull Terriers. Owners and breeders can benefit from this test by identifying at an early age which puppies will have the disease and which will not. Littermates that are either carriers (N/JHC) or clear of the mutation (N/N) are better candidates to retain for breeding purposes. Breeders should avoid mating 2 carriers that can produce affected dogs. Veterinarians can benefit from this test by determining if a clinical cataract case in these breeds has a known genetic etiology.

ORDER TEST KITS | PRICE LIST
Allow 3-6 business days for results.

N/N No copies of JHC mutation. Cataracts may however develop because of other genetic and environmental factors.
N/JHC 1 copy of the JHC mutation. Dog is a carrier. If bred to an N/N dog, 50% of offspring are predicted to be JHC carriers.
JHC/JHC 2 copies of JHC mutation. Dog is affected. If bred, dog will pass on a copy of JHC to all offspring.

 

 

 
Veterinary Genetics Laboratory, Tel 530-752-2211, Email VGL