Genetic testing explained

The MDR1 gene, or multi-drug resistance gene, codes for a protein that is responsible for protecting the brain by transporting potentially harmful chemicals away from the brain. In certain breeds, a mutation occurs in the MDR1 gene that causes sensitivity to Ivermectin, Loperamide, and a number of other drugs. Dogs with this mutation have a defect in the P-glycoprotein that is normally responsible for transporting certain drugs out of the brain. The defective protein inhibits the dog’s ability to remove certain drugs from the brain, leading to a buildup of these toxins. As a result of accumulation of toxins, the dog can show neurological symptoms, such as seizures, ataxia, or even death. Dogs that are homozygous for the MDR1 gene, meaning that they have two copies of the mutation, will display a sensitivity to Ivermectin, and other similiar drugs. Dogs that are heterozygous, meaning they have only one copy of the mutation, can still react to these drugs at higher doses.

The following is a partial list of drugs known to have a negative effect on dogs with the MDR1 mutation:

Acepromzazine, Aldosterone, Amitriptyline, Antiemetics, Apomorphine, Buprenorphine, Butorphanol, Chinidin, Cimeditine, Cortisol, Cysolporin A, Dexamethasone, Digoxin, Diltiazem, Domperidone, Doxorubicin, Doxycycline, Ebastine, Erythromycin, Estradiol, Etoposide, Fentanyl, Fexofenadine, Grepafloxacin, Hydrocortisone, Ivermectin, Itraconazole, Ketoconazole, Loperamide, Losartan, Methylprednisolone, Metoclopramide, Metronidazole, Milbemycin, Mitoxantrone, Morhpine, Moxidectin, Ondansetron, Paclitaxel, Phenothiazines, Phenytoin, Quinidine, Ranitidine, Rifampin, Rifamycin,  Selamectin, Sparfloxacin, Tacrolimus, Tetracycline, Verapamil, Vinblastine, Vincristine

Additional drugs beyond this list could have a negative effect on dogs with the MDR1 mutation and it is recommended to consult a licensed veterinarian for more information.

A (CLEAR/NORMAL): These dogs have two copies of the normal gene and will neither develop MDR1 nor pass this mutation to their offspring.

B (CARRIER/AFFECTED): These dogs have one copy of the normal gene and one copy of the mutation associated with this disease. They can react to certain drugs at higher doses and pass the mutation to 50% of its offspring, on average.

C (AT RISK/AFFECTED): These dogs have two copies of the mutation associated with this disease and which results in sensitivity to a number of drugs including but not limited to Ivermectin, Loperamide, Doxorubicin, Cyclosporin, Digoxin, Acepromazine, Butorphanol and others.

Progressive retinal atrophy (PRA) is a category of different progressive conditions related to retinal atrophy that can eventually lead to blindness.  Progressive rod-cone degeneration (PRA-PRCD) is one specific type of PRA that affects many dog breeds.  It is an inherited eye disease with late onset of symptoms that are due to degeneration of both rod and cone cells of the retina.  These cells are important for vision in dim and bright light.  Most dogs begin to show symptoms of the disease at approximately 3-5 years of age that manifests as difficulty seeing at night (night blindness) and loss of peripheral vision.  Although rate of onset and disease progression can vary by breed, PRA-PRCD typically results in eventual loss of sight and complete blindness in affected dogs.  It is important to note that other inherited eye disorders can display similar symptoms to PRA-PRCD.

A (CLEAR/NORMAL): These dogs have two copies of the normal gene and will neither develop PRA-PRCD nor pass this mutation to their offspring.

B (CARRIER/NOT AFFECTED): These dogs have one copy of the normal gene and one copy of the mutation associated with this disease. They will not develop PRA-PRCD and will, if bred, pass the mutation to 50% of its offspring, on average.

C (AT RISK/AFFECTED): These dogs have two copies of the mutation associated with PRA-PRCD which typically results in complete blindness for most breeds.

Cataracts are a clouding of lens of the eye caused by a breakdown of tissue in the eye. This generally results in an inability to see clearly, and can cause total blindness. In canines, mutations that result in cataracts can be passed to offspring and is known as Hereditary Cataracts (HC), Juvenile Cataracts (JC) or Early Onset cataracts (EOC). A mutation in the HSF4 gene causes this type of cataracts in several breeds of dogs. In this case, the dog is typically affected bilaterally with both eyes affected by the disease. The cataracts associated with HSF4 also occur in the posterior region of the lens. They usually begin small and grow progressively, though the speed of growth is highly variable. Some cataracts will grow so slowly that the dog’s vision remains relatively clear, while others will grow such that the dog will quickly go blind. Corrective surgery is possible, though it is costly and is not always effective. One HSF4 mutation causes the recessive form of HC in Boston Terriers, Staffordshire Bull Terriers, and French Bulldogs. Because it is recessive, a dog must have two copies of this mutation to experience this form of cataracts. This mutation is only responsible for early-onset HC, which typically occur between 12 months and 3 years of age in Staffordshires, and between 2-3 years in Boston Terriers. Boston Terriers can also be afflicted by late-onset HC; however, the HSF4 gene mutation is not responsible for that particular form of cataracts. A separate mutation of the HSF4 gene is responsible for HC in Australian Shepherds. This mutation affects Aussies differently, in that the disease is dominant, but not completely penetrant. This means that only one copy of the mutation is necessary to predispose a dog to the disease, however, incomplete penetrance means that a dog that has this mutation will not always develop HC. Research suggests that the mutation makes a dog 12 times more likely to develop posterior bilateral cataracts at some point in their lifetime. It is likely that a secondary gene interaction occurs in the small percentage of dogs possessing the HC mutation but do not develop cataracts, however, this interaction is not yet know. It is important to note that not all cataracts are hereditary. Cataracts can also be caused by old age or injury. Also, cataracts that occur in different regions of the lens can also be familial, but not necessarily attributed to this gene mutation.

Australian Shepherd:

A (CLEAR/NORMAL): These dogs have two copies of the normal gene and will neither develop HSF4-Hereditary Cataracts nor pass this mutation to their offspring.

B (CARRIER/AT RISK): These dogs have one copy of the normal gene and one copy of the mutation associated with this disease. They will likely develop HC and will, if bred, pass the mutation to 50% of its offspring, on average.

C (AT RISK/AFFECTED): These dogs carries two copies of the mutant gene and are homozygous for HC. The dog will very likely be affected by HSF4-Hereditary Cataracts, and will always pass on a copy of the mutated gene to its offspring.

Degenerative Myelopathy (DM) is a progressive disease of the spinal cord in older dogs. The disease has an insidious onset typically between 8 and 14 years of age. It begins with a loss of coordination (ataxia) in the hind limbs. The affected dog will wobble when walking, knuckle over or drag the feet. This can first occur in one hind limb and then affect the other. As the disease progresses, the limbs become weak and the dog begins to buckle and has difficulty standing. The weakness gets progressively worse until the dog is unable to walk. The clinical course can range from 6 months to 1 year before dogs become paraplegic. If signs progress for a longer period of time, loss of urinary and fecal continence may occur and eventually weakness will develop in the front limbs. Another key feature of DM is that it is not a painful disease.  Although any dog can be tested for DM, it is possible that the genetic background that predominates in some breeds prevents the development of symptoms even in dogs testing affected (at risk).  At this time the required evidence of association between the genetic mutation and actual spinal cord evaluations has only been proven in the breeds listed.

Please see http://www.offa.org/dnatesting/dmexplanation.htmland http://www.caninegeneticdiseases.net/DM/ancmntDM.htm for additional information on DM diagnosis.

A (CLEAR/NORMAL): These dogs have two normal copies of DNA. Among the hundreds of dogs studied to date at the University of Missouri, only two dogs with test results of ‘CLEAR/NORMAL’ have been confirmed to have DM.

B (CARRIER/NOT AFFECTED): These dogs have one copy of the mutation and one normal copy of DNA. Carriers are far less likely to develop DM however; a few cases to date of DM have been confirmed in a small number of carrier dogs.

C (AT RISK/AFFECTED): These dogs have two copies of the mutation and will likely develop DM during their lifetime. Although many dogs tested to date typed as ‘AT RISK/AFFECTED’ have been clinically confirmed DM, recent evidence suggest that there are other causes of DM in some breeds. In addition, not all dogs testing as ‘AT RISK/AFFECTED’ have shown clinical signs of DM. Research is ongoing to estimate what percentage of dogs testing as ‘AT RISK/AFFECTED’ will develop DM within their lifespan. At this point, the DM mutation can be interpreted as being ‘AT RISK’ of developing DM within the animal’s lifetime. For dogs showing clinical signs with a presumptive diagnosis of DM, ‘AT RISK/AFFECTED test results can be used as an additional tool to aid in the diagnosis of DM.

Collie eye anomaly (CEA) is an inherited disease that affects several dog breeds.  It can also be referred to as choroidal hypoplasia (CH) due to the fact that the choroid layer of tissue is thinner in dogs suffering from the disease.  This layer of tissue is responsible for supplying nutrients and blood to the retina.  With insufficient blood flow the choroid does not develop properly and can often lead to retinal detachment and subsequent blindness.  The disease can present itself in both a mild and severe form with symptoms varying between affected dogs.  Dogs with a mild form of the disease can show thinning of the choroid and may maintain normal vision.  Dogs with a more severe version of the disease can have additional eye problems leading to significant vision loss and potentially complete blindness. Although both mild and severe forms of CEA are associated with the same mutation (NHEJ1), predicting disease severity is difficult.

A (CLEAR/NORMAL): These dogs have two copies of the normal gene and will neither develop CEA nor pass this mutation to their offspring.

B (CARRIER/NOT AFFECTED): These dogs have one copy of the normal gene and one copy of the mutation associated with this disease. They will not develop CEA and will, if bred, pass the mutation to 50% of its offspring, on average.

C (AT RISK/AFFECTED): These dogs have two copies of the mutation associated with CEA which can result in a range of symptoms from vision impairment to complete blindness.