Genetic Discovery Finds Dachshunds’ Short-Leg Phenotype Linked To IVDD

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Dachshund breeder MaryAnne Teal of Williamsburg, Virginia, has been around the block more times than she would like dealing with dogs diagnosed with intervertebral disc disease (IVDD). Despite her efforts to study bloodlines and breed away from the debilitating disease known for its high mortality rate and high cost of surgical and veterinary care, Teal has not been successful.

An owner of Smooth Standard Dachshunds for 30 years, Teal adores the breed’s big personality, its long-backed body and short legs. Her love for her Dachshunds is seen in the top-quality care she has given her dogs with IVDD. Decompression surgery and rehabilitation did not always help her dogs regain walking ability. When these efforts did not restore mobility, she outfitted her dogs with carts and her home with ramps and gates to keep them safe.

“IVDD has pretty much affected our lives in every possible way,” Teal says. “We have stressed our own backs and knees lifting and carrying our dogs. It is absolutely heartbreaking when a dog never walks again. Caring for a paralyzed dog is emotionally, financially and physically draining.”

Teal is not alone. Dachshunds have the highest occurrence of IVDD than any other breed, with an estimated disease incidence of 19 to 24 percent,1 thus many breeders and owners can relate to what it’s like to care for a dog affected by IVDD.

Although the cause of IVDD has been a mystery, a common theory has blamed the Dachshund’s long back. A recent breakthrough discovery at the University of California-Davis identified a functional fibroblast growth factor 4 (FGF4) retrogene insertion on canine chromosome 12. The finding is key in helping to explain the causative variant attributed to the chondrodystrophy (CDDY) phenotype in Dachshunds, as well as many other breeds.

“Their backs are not so much long as their legs are short,” says Danika Bannasch, DVM, PhD, the Maxine Adler Endowed Chair of Genetics at UC Davis, whose laboratory made the gene discovery.  

Type I IVDD is most common in Dachshunds. It is an an inherited disorder caused by CDDY, a condition of shorter legs and abnormal intervertebral discs in which the discs degenerate prematurely in young dogs, occurring in some dogs as young as 1 year of age. In contrast, Type II IVDD occurs in older dogs and is usually limited to a single intervertebral disc.

Having a gelatin-like core surrounded by a fibrous coating, the intervertebral discs, located between the vertebrae, protect and cushion the spinal column. In dogs predisposed to Type I IVDD, the discs calcify and harden, which can cause them to herniate into the spinal canal. As the discs press on the nerves of the spinal cord, a dog may experience pain, nerve damage, loss of bladder and bowel control, and/or paralysis. 

In Teal’s experiences, her first dog with IVDD was partially paralyzed after being diagnosed at 2 1/2 years old. Her second dog, a show champion and Hound Group winner, was bred before being affected with IVDD. Although the dog recovered, she produced a daughter that developed IVDD at 4 years old and recovered partially with treatment though she struggled for the rest of her life with ataxia, or muscle incoordination.

“The FGF4-12 retrogene insertion in the dog genome that is responsible for CDDY is characterized by short legs due to dysplastic, shortened long bones and susceptibility to Type I IVDD across several dog  breeds,” Dr. Bannasch says.

An earlier FGF4-retrogene insertion discovery on canine chromosome 18 explains a short-legged phenotype known as chondrodysplasia (CDPA) that also occurs in several breeds, including Dachshund, Basset Hound, Pembroke Welsh Corgi, Pekingese, Scottish Terrier, West Highland White Terrier, and Cairn Terrier. The identification of the FGF4-18 insertion was made in 2009 by a research team at the National Institutes of Health studying breed sizes and morphology.

“The chondrodystrophy-associated mutation occurred a long time ago,” says Emily Brown, PhD, DVM, a genetics graduate student in Dr. Bannasch’s laboratory who contributed to the UC Davis research. “There are descriptions of short-legged dogs dating over 4,000 years ago. Both the FGF4-12 and FGF4-18 mutations occur concurrently in unrelated dog breeds from diverse breed groups and geographical locations.”

Dwarfism & Abnormal Intervertebral Discs

A fascinating aspect of the domestication of the dog from the wolf is the subsequent variation in size and shape of purebred dog breeds that has transpired from dog breeding and selection. One of the most extreme examples of dog breed differences is in limb length, with extremely short limbs defining many breeds.

Extensive examination of growth plates has been performed on many short-legged breeds, such as Dachshund, Pekingese, French Bulldog, American Cocker Spaniel, and Beagle, as these breeds also are prone to IVDD. Histopathological analysis of the bones of puppies from these breeds has shown that their short stature is due to defects in endochondral ossification, the process whereby cartilage is replaced by bone in the developing limb.

“Dwarfism caused by chondrodystrophy has long been known to be associated with abnormal intervertebral discs,” Dr. Bannasch says. “A reduction of long bone growth occurs due to defects in endochondral ossification. These early changes in the structure of growth plates cause shorter legs and can also impact dogs through premature degeneration of the intervertebral discs.” 

The FGF4-12 insertion mutation causing CDDY affects height phenotype in a semi-dominant inheritance, whereby dogs with two copies of the mutation are smaller than those with one copy. The mutation impacts the IVDD phenotype with a dominant inheritance, thus dogs only require one copy of the retrogene insertion to be predisposed.

Interestingly, some, but not all, CDPA-affected breeds are at increased risk for IVDD. For example, neither the Cairn Terrier nor the West Highland White Terrier has IVDD. The autosomal dominant inheritance of the FGF4-18 insertion means dogs need only one gene copy from a sire or dam to inherit CDPA. Notably, some dogs have both FGF4-12 and FGF4-18 mutations, which result in a more drastic reduction of leg length.

Similarly, in humans, mutations in the FGF family of genes (FGFR3) cause achondrodysplasia, the most common dwarfism in people and a type of chondrodystrophy that prevents bones from growing as long as they should. The disorder is linked to shortened limbs and abnormal vertebrae associated with intervertebral disc disease. FGF genes are involved in several embryological development processes in humans and are key for appropriate growth and development.

Odd though it may seem, a medium-legged breed, the Nova Scotia Duck Tolling Retriever, helped the researchers discover the FGF4-12 mutation that predisposes Dachshunds, as well as many other breeds, to short legs and IVDD. The idea of using Tollers, the smallest of the retriever breeds, was because they are commonly affected by a form of skeletal dysplasia that causes short-legged individuals and abnormalities such as long-bone bowing, physeal (growth plate) widening and joint incongruity.

“Using a genome-wide association study (GWAS), we compared 13 Tollers with severe skeletal dysplasia and 15 Toller controls without severe skeletal dysplasia,” says Dr. Bannasch. “To our surprise, we found the short-legged Tollers had an FGF4 retrogene insertion on canine chromosome 12 similar to the one found previously on chromosome 18 in some short-legged breeds.

“Since the skeletal dysplasia phenotype is not uncommon among dog breeds, we investigated haplotype sharing across breeds and saw that a portion of this haplotype, or genetic variance, was shared with Beagles and American Cocker Spaniels, two breeds considered classically chondrodystrophic.”

In order to determine if the same region was associated with IVDD, the researchers performed a second GWAS for Type I disc disease across breeds including mixed breeds and found, indeed, the same region was associated.

To pinpoint the causative variant for skeletal dysplasia and IVDD, they sequenced the genomes of one skeletal dysplasia-affected Toller, one IVDD-affected Dachshund and 83 unaffected controls.

“We found that this second FGF4 retrogene insertion in the canine genome is not only responsible for skeletal dysplasia in Tollers but also for chondrodystrophy, including the predisposition to Type I IVDD across all dog breeds,” Dr. Bannasch continues.

The research team looked at other breeds that are considered chondrodysplastic and found the same mutation on chromosome 12 in the Dachshund, Beagle, American Cocker Spaniel, a short-legged Coton de Tulear, French Bulldog, Maltese, Pekingese, Pembroke Welsh Corgi, and a short-legged Miniature Poodle. Some of the breeds, such as Dachshund, had mutations on both chromosome 12 and chromosome 18.

The chromosome 12 mutation that causes CDDY is found in more breeds than the chromosome 18 mutation that causes CDPA. Other breeds with the FGF4-12 retrogene insertion are: Basset Hound, Bichon Frise, Cardigan Welsh Corgi, Cavalier King Charles Spaniel, Chesapeake Bay Retriever, Chihuahua, Dandie Dinmont Terrier, English Springer Spaniel, Jack Russell Terrier, Nova Scotia Duck Tolling Retriever, Toy Poodle, Portuguese Water Dog, Scottish Terrier, and Shih Tzu.

“We realized that the long-held belief that all short-legged ‘dwarf’ dogs result from the same chondrodysplasia condition is wrong,” says Dr. Bannasch. “There are two independent genetic mutations caused by separate mutations of the same retrogene that cause slightly different types of dwarfism. It may have to do with the surrounding chromosomal region that drives expression in the developing disc. Chondrodysplasia is due to the FGF4-18 insertion mutation, and chondrodystrophy is caused by the FGF4-12 insertion.”

Impact on Breeding

Dachshund breeders may wonder whether it is possible to select against the CDDY mutation that predisposes dogs to IVDD, while keeping the CDPA mutation and the breed’s desirable short legs.

“The most important factor is how widespread the FGF4-12 mutation is in the gene pool, as there must be sufficient variation at that locus in order to breed away from IVDD,” explains Dr. Bannasch. “I think it is important for breeders to understand that the FGF4-12 mutation is very common in most of the predisposed breeds.”

In the Dachshund, the FGF4-18 retrogene insertion is fixed, which means all Dachshunds have this mutation, she says. However, only those that also have the FGF4-12 mutation are affected with IVDD or at increased risk for IVDD. Thus, some dogs can have short legs and normal discs, while others may have short legs and abnormal discs.

“Although this finding is exciting, it is premature to think it will quickly solve the problem of IVDD in Dachshunds,” Dr. Bannasch says. “We are not sure how common or genetically set chondrodystrophy is across Dachshund sizes, so selection against it should be done very slowly and may not even be possible if CDDY is homozygous.”

Given the high mortality rate of IVDD combined with the high cost of care and surgery, the FGF4-12 retrogene insertion discovery provides important insights, though more research is needed to better understand its impact on a breed-specific level. Dr. Bannasch and her team are eager to collect more genetic samples and continue the work.

“We are optimistic that someday there will be more hope for Dachshunds and an ability to breed away from IVDD,” Teal says. “This has been a difficult, heartbreaking journey for us, but our love for our dogs has carried us through.” 

1 Ball MU, McGuire JA. Swaim SF, et al. Patterns of Occurrence of Disk Disese Among Registered Dachshunds. Journal of the American Veterinary Association. 1982;180:519-522. Purina appreciates the support of the Dachshund Club of America and particularly Charlotte Borghardt, chair of the DCA Health Committee, in helping to identify topics for the Dachshund Update.

Genetic Testing For IVDD Risk & Submitting Samples For Further Study

A DNA test is available for chondrodystrophy (CDDY) and chondrodysplasia (CDPA) at the University of California-Davis Veterinary Genetics Laboratory (VGL). The test can be ordered online.

The VGL reports test results and their interpretations as follows:

CHONDRODYSTROPHY (CDDY & IVDD RISK)

N/N                       No copies of CDDY mutation

N/CDDY              One copy of CDDY mutation. Dog is at risk for IVDD. Mutation
                              causes leg shortening compared to N/N dogs. When bred to an N/N dog,
                              this will produce 50 percent of normal-sized puppies and 50 percent of
                              puppies at risk for IVDD.

CDDY/CDDY      Two copies of CDDY mutation. Dog is at risk for IVDD. Mutation
                              causes leg shortening compared to N/N dogs. Will produce 100 percent
                              of puppies with shorter legs at risk for IVDD.

CHONDRODYSPLASIA (CDPA)

N/N                       No copies of CDPA mutation

N/CDPA               One copy of CDPA. Mutation causes leg shortening compared to N/N
                              dogs.

CDPA/CDPA       Two copies of CDPA. Mutation causes leg shortening compared to
                              N/N dogs.

 

 

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