Collaboration Aids Discovery of SLC13A1 Mutation for Dwarfism in Miniatures
The recent discovery of the gene mutation that causes a crippling dwarfism in Miniature Poodles, and the subsequent development of a direct DNA test to identify carriers, represents a successful collaboration between breeders and researchers.
Mark Neff, Ph.D., director of the Program for Canine Health and Performance at the Van Andel Institute in Grand Rapids, Mich., found that partial deletion of the sulfate transporter SLC13A1 causes the recessive inherited defect in Miniature Poodles. Without appropriate levels of sulfate, a puppy’s bones and cartilage cannot develop normally. Affected puppies appear normal at birth, but at 3 weeks of age stunted growth and abnormal movement are apparent.
The condition is known as osteochondrodysplasia (OC), which describes a broad group of cartilage and bone disorders stemming from structural, metabolic and endocrinological causes. Affected Miniature Poodle puppies develop extended hind limbs, enlarged joints, flattening of the rib cage, shortened and bent long bones, undershot jaws, and misshapen paws resembling clubfoot. Most puppies are euthanized.
The behind-the-scenes efforts of three dedicated Miniature Poodle breeders collecting DNA samples, including from their own dogs, and canvassing breeders to find affected dogs helped to advance the research. The eight-year initiative culminated with the discovery of the gene mutation last December.
Alison Ruhe, director of projectDOG, a recently founded nonprofit genetic testing and research organization in Albany, Calif., which offers the OC test, says the candidness with which the Miniature Poodle breeders shared their experiences of producing puppies with OC was exemplary. “They truly are models of what breeders should be about,” she says. “Their focus from the beginning was discovering what causes this health disorder. They were open, proactive, practical, empathetic, and not driven by ego or profit.”
The contributing Miniature Poodle breeders are Leslie Newing of Random Wind Poodles in Fairfield, Conn., Mildred Bartlett of Maestoso Poodles in Oregon, Ill., and Eva Marie Mitchell of Dreem Poodles in Granger, Ind. Several others helped support the research as well.
An Inconsistent Disorder
The first known case of OC in a Miniature Poodle was documented in Britain in 1956. Although OC has been reported in Standard Poodles, Ruhe says projectDOG has not tested any affected Standard or Toy Poodles. The disorder can occur in a variety of forms, and the level of disability is not consistent. Some less affected puppies have survived into adulthood. As they age, their bones may strengthen despite an increased incidence of osteoarthritis.
“We don’t know why some puppies are more affected than others,” Ruhe says. “It is possible that some cases are really another condition altogether. This is why the genetic test is valuable. We can now determine whether a dog truly has hereditary OC.”
When Newing and Bartlett first contacted Neff about osteochondrodysplasia, he was associate director of the Veterinary Genetics Laboratory at the University of California-Davis. He continued the OC project after moving to the Van Andel Institute in Michigan in 2009.
Newing, who has bred Miniature Poodles and Doberman Pinschers with her mother, Suzanne Newing, for 36 years, was aware of two dwarf puppies sired by one of her stud dogs in separate litters born many years ago. Nine years ago, the gene mutation resurfaced in one of her own breedings.
As commonly occurs, the litter appeared normal until the puppies were 3 weeks old. Then, a bitch puppy began to look different. “At 4 weeks old, this puppy stood as though she were in ballet first position,” Newing says. “Her front feet pointed in opposite directions, and she couldn’t support herself or sit up.”
Radiographs confirmed the diagnosis of OC, and the puppy was euthanized. “It doesn’t leave your mind once you’ve seen OC,” says Newing. “You plan, set goals and look forward to a litter, and then this happens.”
Her veterinarian told her about research of dwarfism at the University of Pennsylvania. Donald Patterson, D.V.M., the founder of the school’s veterinary genetic clinic, the first in the country, had studied OC in white Miniature Poodles but was unable to come up with enough dogs to identify the genetic marker. Patterson had since retired and passed away. Newing wasn’t sure where to turn for help, until she received a phone call from Mitchell.
Mitchell also had produced dwarfism in a litter. “There were four puppies in the litter,” she recalls. “The dam ignored three of them and would keep taking the fourth out of the whelping box to care for it.”
Mitchell chided the dam for being a “bad mother.” As the puppies developed, she began to see differences in the three puppies the dam didn’t want to nurse. At 3 weeks old, the puppies were up on their legs, with their eyes open, responding to sounds and playing. However, their front feet were beginning to turn out. A few days later, the puppies appeared deformed.
“It was like they had walnuts for joints,” Mitchell says. “Their joints were hard and rounded, and they yelped a lot.”
The puppies began to have difficulty breathing and spent most of each day lying on their sides. They had to be bottle-fed and had lost their sense of hearing. The three puppies had to be euthanized. Two were sent to the University of Minnesota for necropsy, which confirmed OC.
“Their cartilage had turned to bone,” Mitchell explains. “That’s why they couldn’t hear. Hardening of the cartilage on the ends of their rib cage made it difficult for them to breathe.”
The fourth puppy continued to develop normally, but Mitchell neutered and placed him in a pet home. Devastated, she felt she had to do something. She published an article about her litter, complete with pictures, in Poodle Variety.
Mitchell learned that Neff might be interested in studying OC, so she contacted him at the University of California-Davis. He agreed to take it on but would need samples of DNA from at least 10 unrelated affected dogs to do the research.
“I collected cheek swabs from all my dogs, including the dam and the surviving puppy,” Mitchell says.
Meanwhile, Bartlett, who had shown dogs for more than 60 years, had a litter sired by an English import that included puppies with OC. It wasn’t her first experience with OC. In 1965, a veterinarian asked her to care for an 8-week-old puppy brought to him for euthanasia. Bartlett was struck by the Poodle’s intelligence and disposition.
She had three veterinarians examine the female puppy. No one recognized the disorder, until radiographs confirmed OC when the puppy was older. Bartlett swam the puppy in a harness in her bathtub to strengthen her legs and eventually placed her with friends. The dwarf puppy lived to be 18 years old.
Bartlett travels to dog shows around the country with one of the affected Poodles from the litter that prompted her involvement in the OC research. “Bitzie,” a 5-year-old brown female Miniature, even went to this year’s Poodle Club of America (PCA) National Specialty. “She’s a kind of ‘show and tell.’ I want everyone to see her and understand what the condition is,” Bartlett says.
Now that the DNA test is available, Bartlett routinely screens dogs before breeding. Recently, she bred a tested carrier male, a son of the English import, to a tested clear bitch, producing clear puppies. She appropriately named one Maestoso’s Leap of Faith, who already is a puppy show champion.
OC has a simple autosomal recessive mode of inheritance, meaning that a dog must have two copies of the mutation to be affected. If a carrier is bred to a clear dog, the resulting puppies may be carriers or clear, but none will be affected.
Breeders Making a Difference
Newing, Mitchell, and Bartlett agree that it wasn’t easy to find the affected Miniature Poodles that Neff needed for his research. Some breeders told them that they had never seen nor heard of the condition and couldn’t possibly have it in their lines. Some were angry when they were contacted, even on an informational basis.
“All samples went directly to Dr. Neff,” Newing says. “I didn’t know or want to know who was submitting cheek swabs or what the results were. It was hard to get people to admit there was a problem, but there’s no shame in producing a dwarf puppy. The only disgrace is when you don’t deal with a problem ethically.”
Ruhe emphasizes the need for breeder involvement. “Few, if any, researchers today maintain colonies of dogs for research,” she says. “We need to obtain our DNA samples from breeders and owners. To be successful, we need an engaged breeder community.”
Though it took eight years to obtain the samples, the mutation was identified based on eight affected and eight clear Miniature Poodles. “We used samples from dogs with a common ancestor in the first three generations, but only to validate the test,” Ruhe says. “The Poodles in the original study could not have a grandparent in common.”
Neff’s research was published in PLoS, an open access online journal, in December 2012. The article was titled “Partial Deletion of the Sulfate Transporter SLC13A1 Is Associated with an Osteochondrodysplasia in the Miniature Poodle Breed.”
“Dr. Neff felt that it was important for the entire article to be available online to breeders and owners at no cost,” Ruhe says.
“My greatest honor was being thanked at the end of Dr. Neff’s research article. I so appreciated it. His work made it possible for me to continue breeding,” Bartlett says.
Along with Bartlett, Neff credited Newing, Mitchell, and Dianne Flanagan of South Holland, Ill., for their assistance in finding affected Miniature Poodles.
The DNA test for osteochondrodysplasia is the first genetic test to be distributed by projectDOG. The testing laboratory plans to add genetic marker tests as they become available. “These are tests where we have a good idea of the genetic markers, but we are not yet ready to publish our research results,” Ruhe says. “Our goal is to make accurate, affordable genetic tests available as soon as they are ready.”
Donated laboratory space and equipment, plus generous private donations, allows projectDOG to test DNA for OC at no cost, though donations of $20 to $40 per test are requested. Support from the PCA Foundation allowed for the distribution of 400 test kits at the PCA National Specialty last April. About half of the tests have been returned for free testing. A campaign is planned to encourage Miniature Poodle breeders and owners to return DNA samples from the remaining tests. With more samples, a better idea of the frequency of the OC gene mutation can be determined.
“So far, it looks as though perhaps 10 percent of Miniature Poodles carry the mutation,” says Ruhe. “However, the first breeders to send in tests are probably the ones most likely to have a problem, so it may not be an accurate percentage. We need more subjects to be certain.”
If the DNA test had been available a few years ago, Mitchell could have selectively bred the unaffected puppy from the litter with three dwarfs. “When I swabbed him, he came back clear,” she says. “But I had no way of knowing he was clear at the time, and so he was neutered.”
With help from dedicated breeders and owners, there is no limit to what can be accomplished. “We should all look to better the breed and to be sure our breed has a future,” Mitchell says. “DNA tests are an invaluable tool to do just that.”
Purina appreciates the support of the Poodle Club of America and particularly Elly Holowaychuk, D.V.M., and Leslie Newing, editor of The Poodle Papers, in helping to identify topics for the Purina Pro Club Poodle Update newsletter.
How to Test Miniature Poodles for OC
Miniature Poodles may now be tested for the crippling dwarfism disorder osteochondrodysplasia (OC). A new genetic testing laboratory, projectDOG, offers a direct DNA test that identifies carriers of the recessive inherited disorder.
For information, go to projectdog.org and click on “get a DNA test.” You also may call 510-900-3899 for information. projectDOG requests donations of $20 to $40 per test, but testing is provided free of charge upon request.
Results may be listed for a fee on the website of the Orthopedic Foundation for Animals. Testing for osteochondrodysplasia is not a health requirement for Miniature Poodles to earn Canine Health Information Center (CHIC) certification.
Read about the Research
The scientific article about the discovery of the gene mutation for osteochondrodysplasia is available on an open access online journal. To read the article on the PLoS website, go to plosone.org/article/ info:doi/10.1371/journal.pone.0051917