Health Pre-Screening

Arrhythmogenic right ventricular cardiomyopathy (ARVC), also known as Boxer cardiomyopathy, is an inherited condition in dogs that can cause congestive heart failure and potentially sudden death. The average age at onset of clinical signs and/or Holter monitor abnormalities is approximately 6 years, however, this can vary widely. Clinical signs include coughing and shortness of breath and/or ventricular premature complexes (VPCs). It is important to note that the presence of VPCs is not a conclusive diagnosis of ARVC as other conditions can cause VPCs as well including cardiac muscle inflammation secondary to infectious and neoplastic causes. ARVC in humans has been linked to over 140 mutations in 8 separate genes, thus it is possible that there may be more than one genetic cause of ARVC in dogs. A genetic mutation that causes ARVC was found by researchers at Washington State University. The mutation is in the striatin gene which is located on canine chromosome 17. The striatin gene encodes for a protein that is localized in the cardiac myocyte along with three desmosomal proteins that can be causative for ARVC in humans.

ARVC is a semi-dominant disorder meaning that dogs that inherit one or two copies of the striatin mutation can show clinical signs of ARVC. Dogs with two copies of the mutation had an overall greater number of VPCs, however, they may not necessary develop VPCs or other clinical signs at an earlier age compared to dogs with one copy of the mutation. It is also important to note, that ARVC has variable penetrance meaning that some dogs that carry the mutation may develop the disease at a much later age or may not show clinical signs at all.

Mixed-breed dogs that have inherited at least one copy of this striatin mutation can also develop ARVC. Educating clients with dogs who are susceptible to ARVC is important so they can consider Holter monitoring, recognize the clinical signs, and care for their dogs appropriately.

For more information on ARVC and testing for the striatin mutation:
http://www.cvm.ncsu.edu/vhc/csds/vcgl/boxer-arvc.html

References:
Meurs KM, Mauceli E, Lahmers S, Acland GM, White SN, Lindblad-Toh K. Genome-wide association identifies a deletion in the 3' untranslated region of striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy. Human Genetics, 2010; 128:315-24.

Scansen BA, Meurs KM, Spier AW, Koplitz S, Baumwart RD. Temporal variability of ventricular arrhythmias in Boxer dogs with arrhythmogenic right ventricular cardiomyopathy. Journal of Veterinary Internal Medicine, 2009; 23:1020-4.

Baumwart RD, Meurs KM, Raman SV. Magnetic resonance imaging of right ventricular morphology and function in boxer dogs with arrhythmogenic right ventricular cardiomyopathy. Journal of Veterinary Internal Medicine, 2009; 23:271-4.

Basso C, Fox PR, Meurs KM, Towbin JA, Spier AW, Calabrese F, Maron BJ, Thiene G. Arrhythmogenic right ventricular cardiomyopathy causing sudden cardiac death in boxer dogs: a new animal model of human disease. Circulation, 2004; 109:1180-5.

Spier AW, Meurs KM. Assessment of heart rate variability in Boxers with arrhythmogenic right ventricular cardiomyopathy. Journal of the American Veterinary Medical Association, 2004; 224:534-7.

Boujon CE, Amberger CN. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) in a Boxer. Journal of Veterinary Cardiology, 2003; 5:35-41.

Canine Leukocyte Adhesion Deficiency (CLAD) is a rare but devastating condition that results in a fatal immunodeficiency disease. Dogs affected with CLAD usually die early in life from multiple severe infections, even when treated with massive doses of antibiotics. The clinical manifestations of CLAD are very similar to LAD in humans and BLAD in cattle and all these disorders are caused by mutations in the same gene. The genetic mutation that causes CLAD was identified by researchers at Uppsala University in Sweden. The mutation is in the beta-2 integrin subunit (ITGB2) of CD18 and is located on canine chromosome 31.

CLAD is a recessively inherited disorder meaning that dogs must inherit two copies of the mutated ITGB2 gene to be at risk of developing the clinical signs. To date, the ITGB2mutation has been identified in the Irish Setter and Irish Red and White Setter.

Mixed-breed dogs that have inherited two copies of this mutation can also develop CLAD. Educating clients with dogs who are susceptible to CLAD is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on CLAD and testing for the ITGB2 mutation:
http://www.optigen.com/opt9_test_clad.html

References:
Kijas JM, Bauer TR Jr, Gafvert S, Marklund S, Trowald-Wigh G, Johannisson A, Hedhammar A, Binns M, Juneja RK, Hickstein DD, Andersson L. A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency. Genomics. 1999 Oct 1;61(1):101-7.

Foureman P, Whiteley M, Giger U. Canine leukocyte adhesion deficiency: presence of the Cys36Ser beta-2 integrin mutation in an affected US Irish Setter cross-breed dog and in US Irish Red and White Setters. J Vet Intern Med. 2002 Sep-Oct;16(5):518-23.

Centronuclear Myopathy (CNM), previously known as Labrador Retriever myopathy, is an inherited condition in dogs that can cause a low head carriage (ventroflexion), muscular weakness, difficulty eating, and a stiff, stilted gait. They may also show an arched back and bunny-hopping gait with exercise. The age of onset of clinical signs is variable between 6 weeks and 6 months with most dogs showing clear signs between 3 to 4 months of age. Exercise, excitement, and even cold temperatures may exacerbate the clinical signs and may lead to collapse. There may also be marked muscle atrophy in affected dogs, particularly in the fore limbs and the muscles of mastication. A genetic mutation that causes CNM was found by researchers at Alfort School of Veterinary Medicine in France. CNM is caused by a short interspersed repeat element (SINE) that has been inserted in exon 2 of the protein tyrosine phosphatase-like member A (PTPLA) gene which is located on canine chromosome 2.

CNM is a recessive disorder meaning that dogs must inherit two copies of the mutated PTPLA gene to be at risk of developing the clinical signs. To date, the CNM mutation in PTPLA has been identified exclusively in Labrador Retrievers.

Mixed-breed dogs that have inherited two copies of this mutation can also develop CNM. Educating clients with dogs who are susceptible to CNM is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on CNM and testing for the PTPLA mutation:
http://www.vetgen.com/canine-centronuclear-myopathy.html

References:
Gentilini F, Zambon E, Gandini G, Rosati M, Spadari A, Romagnoli N, Turba ME, Gernone F. Frequency of the allelic variant of the PTPLA gene responsible for centronuclear myopathy in Labrador Retriever dogs as assessed in Italy. Journal of Veterinary Diagnostic Investigation, 2011; 23:124-6.

Pelé M, Tiret L, Kessler JL, Blot S, Panthier JJ. SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dogs. Human Molecular Genetics, 2005; 14:1417-27.

Tiret L, Blot S, Kessler JL, Gaillot H, Breen M, Panthier JJ. The cnm locus, a canine homologue of human autosomal forms of centronuclear myopathy, maps to chromosome 2. Human Genetics, 2003; 113:297-306.

Cone degeneration (CD) disease causes day blindness due to degeneration of the retinal "cones" - cone-shaped cells in the retina that respond primarily to bright daylight. CD affects German Shorthair Pointers and can be diagnosed in the early weeks of life. Between 8 and 12 weeks of age, when retinal development is normally completed in dogs, signs of vision problems are noticeable. The pups become day-blind and are photophobic - meaning that exposure to bright light is irritating or even painful, so much so that the pup will shun brightly-lit areas. Vision in dim light remains normal as the "rods" - rod-shaped cells that respond to dim light - are not involved in this disease. The retina of the affected dog initially appears normal when examined by an ophthalmologist and initially the ERG (electroretinogram) recording is normal. However, the ERG response from the degenerating cones declines with age and is non-recordable in the mature CD-affected dog. The genetic mutation that causes CD was found by researchers at Cornell University. The mutation is in the cyclic nucleotide-gated channel beta-subunit (CNGB3) gene which is located on canine chromosome 29.

CD is a recessively inherited disorder meaning that dogs must inherit two copies of the mutated CNGB3 gene to be at risk of developing the clinical signs. To date, this CD mutation has been identified in the German Shorthair Pointer.

Mixed-breed dogs that have inherited two copies of this mutation can also develop CD. Educating clients with dogs who are susceptible to CD is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on CD and testing for the CNGB3 mutation:
http://www.optigen.com/opt9_test_cd.html

References:
Sidjanin DJ, Lowe JK, McElwee JL, Milne BS, Phippen TM, Sargan DR, Aguirre GD, Acland GM, Ostrander EA. Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum Mol Genet. 2002 Aug 1;11(16):1823-33.

Congenital hypothyroidism with goiter is an autosomal recessive condition initially identified in Toy Fox Terriers. Affected puppies show inactivity, abnormal hair coat, stenotic ear canals, delayed eye opening, and have a palpably enlarged thyroid gland by one week of age. They have low thyroid hormone levels and consequently have high thyroid-stimulating hormone concentrations. Treatment with oral thyroid hormone replacement therapy is effective and results in near-normal growth and development. A nonsense mutation in the thyroid peroxidase (TPO) gene was identified by researchers at Michigan State University. The TPO gene is located on canine chromosome 17.

Congenital hypothyroidism with goiter is a recessively inherited disorder meaning that dogs must inherit two copies of the mutated TPO gene to be at risk of developing the clinical signs. To date, the TPO mutation has been identified in the Toy Fox Terrier and Rat Terrier.

Mixed-breed dogs that have inherited two copies of this mutation can also develop congenital hypothyroidism with goiter. Educating clients with dogs who are susceptible to congenital hypothyroidism is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on congenital hypothyroidism with goiter and testing for the TPO mutation:
http://www.mmg.msu.edu/faculty/fyfe/fyfeCHGtesting.pdf

References:
Fyfe JC, Kampschmidt K, Dang V, Poteet BA, He Q, Lowrie C, Graham PA, Fetro VM. Congenital hypothyroidism with goiter in toy fox terriers. Journal of Veterinary Internal Medicine, 2003; 17:50-7.

Congenital Stationary Night Blindness (CSNB), also known as hereditary retinal dystrophy, congenital night blindness with varying degrees of visual impairment in affected dogs ranging from normal day vision to profound day blindness. Profound visual impairment may be present at a very young age (5-6 weeks). An abnormal ERG (electroretinogram) recording can also be observed with severely depressed rod and cone mediated responses. The genetic mutation that causes CSNB was confirmed by researchers at Cornell University. The mutation is in the retinal pigment epithelium-specific protein 65kD (RPE65) gene which is located on canine chromosome 6. This mutation causes retinal dysfunction and accumulation of lipid vacuoles in the retinal pigment epithelium. Mutations in the RPE65 gene are also responsible for childhood-onset severe retinal dystrophy in humans, thus the dog is a model of this human disease. To determine the efficacy of gene therapy to treat this type of genetic disorder in a non-rodent model, a retrovirus containing the wild-type RPE65 gene was used to restore vision in a dog with CSNB.

CSNB is a recessively inherited disorder meaning that dogs must inherit two copies of the mutated RPE65 gene to be at risk of developing the clinical signs. To date, the CSNB mutation has been identified in the Briard.

Mixed-breed dogs that have inherited two copies of this mutation can also develop CSNB. Educating clients with dogs who are susceptible to CSNB is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on CSNB and testing for the RPE65 mutation:
http://www.optigen.com/opt9_test_csnb.html

References:
Aguirre GD, Baldwin V, Pearce-Kelling S, Narfstrom K, Ray K, Acland GM. Congenital stationary night blindness in the dog: common mutation in the RPE65 gene indicates founder effect. Molec Vision 1998 4: 23.

Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, Pearce-Kelling SE, Anand V, Zeng Y, Maguire AM, Jacobson SG, Hauswirth WW, Bennett J. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001 May;28(1):92-5.

Copper toxicosis (CT) refers to a group of diseases where copper accumulates and results in severe liver disease in several dog breeds. Without anti-copper treatment, affected dogs can die between three and seven years of age. The cause of copper accumulation is still being researched in most breeds. One mutation has been identified in Bedlington Terriers and a second mutation in the same gene may also exist; research is on-going. The identified CT mutation in Bedlington Terriers is in a copper metabolism gene, COMMD1, located on canine chromosome 10. The genetic mutation that causes CT in Bedlington Terriers was originally found by researchers at Utrecht University, and later a diagnostic DNA test for the mutation was developed at the Animal Health Trust.

CT is a recessively inherited disorder meaning that dogs must inherit two copies of the mutated COMMD1 gene to be at risk of developing the clinical signs. To date, the COMMD1 mutation has been identified in the Bedlington Terrier.

Mixed-breed dogs that have inherited two copies of this mutation can also develop CT. Educating clients with dogs who are susceptible to CT is important so they can recognize the clinical signs, care for their dogs appropriately, and institute dietary therapy.

For more information on CT and testing for the COMMD1 mutation:
http://www.vetgen.com/canine-ct-marker.html

References:
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. Characterization of the COMMD1 (MURR1) mutation causing copper toxicosis in Bedlington terriers. Animal Genetics, 2005; 36:497-501.

Cyclic neutropenia, also known as ‘gray collie syndrome", is a disease caused by a dramatic loss of neutrophils in a cyclical pattern approximately every 10 to 12 days. During the periods of neutropenia, affected dogs are more susceptible to infectious diseases and develop clinical signs such as fever, diarrhea, joint pain, or other clinical signs associated with eye, respiratory, or skin infections. They may also be prone to bleeding episodes. Affected puppies are smaller and weaker with a noticeable pale gray, pinkish/gray or beige color. These puppies generally die within a few days; those that do survive are susceptible to a variety of infections. Proper treatment may extend life to 2 to 3 years. The genetic mutation that causes cyclic neutropenia is in the adaptor protein complex 3 (AP3) ß-subunit gene which is located on canine chromosome 20. Mutations in a related gene, neutrophil elastase (ELA2), are also responsible for types of cyclic neutropenia in humans.

Cyclic neutropenia is a recessively inherited disorder meaning that dogs must inherit two copies of the mutated AP3 gene to be at risk of developing the clinical signs. To date, the AP3 mutation has been identified in the Collie.

Mixed-breed dogs that have inherited two copies of this mutation can also develop cyclic neutropenia. Educating clients with dogs who are susceptible to cyclic neutropenia is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on cyclic neutropenia and testing for the AP3 mutation:
http://www.vetgen.com/canine-cyclic-neutropenia.html

References:
Benson KF, Li FQ, Person RE, Albani D, Duan Z, Wechsler J, Meade-White K, Williams K, Acland GM, Niemeyer G, Lothrop CD, Horwitz M. Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastase. Nature Genetics, 2003; 35:90-6.

Degenerative myelopathy (DM) is a slowly progressive disease that causes the loss of coordination in the hind limbs and increasing weakness. Clinical signs become evident after approximately 5 years of age and are due to the loss of myelin and axons in the lateral white matter of the spinal cord as a result of anti-superoxide dismutase 1 antibody accumulation. These clinical and pathologic signs closely resemble amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, in humans and DM represents the first recognized spontaneously occurring animal model for this disease. The genetic mutation that causes DM is in the superoxide dismutase (SOD1) gene which is located on canine chromosome 31. Mutations in SOD1 are also responsible for some cases of ALS in humans.

DM is a recessively inherited disorder meaning that dogs must inherit two copies of the mutated SOD1 gene to be at risk of developing the clinical signs. To date, the SOD1 mutation has been identified in the American Eskimo, Bernese Mountain Dog, Boxer, Cardigan Welsh Corgi, Chesapeake Bay Retriever, German Shepherd Dog, Golden Retriever, Great Pyrenees, Kerry Blue Terrier, Pembroke Welsh Corgi, Standard Poodle, Pug, Rhodesian Ridgeback, Shetland Sheepdog, Soft Coated Wheaten Terrier, and Wire Fox Terrier.

Mixed-breed dogs that have inherited two copies of this mutation can also develop DM. Educating clients with dogs who are susceptible to DM is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on DM and testing for the SOD1 mutation:
http://www.offa.org/dnatesting/dm.html

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. Proceedings of the National Academy of Sciences USA, 2009; 106:2794-9.

Clark LA, Tsai KL, Murphy KE. Alleles of DLA-DRB1 are not unique in German Shepherd dogs having degenerative myelopathy. Animal Genetics, 2008; 9:332.

Barclay KB, Haines DM. Immunohistochemical evidence for immunoglobulin and complement deposition in spinal cord lesions in degenerative myelopathy in German Shepherd dogs. Canadian Journal of Veterinary Research; 1994; 58:20-24.

Averill DR Jr. (1973) Degenerative myelopathy in the aging German Shepherd dog: clinical and pathologic findings. Journal of the American Veterinary Medical Association, 1973; 162:1045-51.

Cataracts are a leading cause of blindness in dogs and there are a number of inherited conditions that cause cataracts. In most cases, the genetic mutation causing inherited cataracts is recessively inherited, however, Australian Shepherds have a form of hereditary cataracts with a dominant mode of inheritance. The genetic mutation that causes dominant hereditary cataracts was identified by researchers at the Animal Health Trust. The HSF4 gene is located on canine chromosome 5. Note that other mutations in HSF4 have been associated with other forms of cataracts in dogs.

Dominant hereditary cataracts is a dominant disorder meaning that dogs that inherit at least one copy of the mutated HSF4 gene are at risk of developing the clinical signs. To date, the dominant hereditary cataract mutation in HSF4 has been identified in Australian Shepherds.

Mixed-breed dogs that have inherited at least one copy of this mutation can also develop dominant hereditary cataracts. Educating clients with dogs who are susceptible to hereditary cataracts is important so they can recognize the clinical signs and care for their dogs.

For more information on dominant hereditary cataracts and testing for the HSF4 mutation:
http://www.aht.org.uk/genetics_hcas.html

References:
Mellersh CS, McLaughlin B, Ahonen S, Pettitt L, Lohi H, Barnett KC. Mutation in HSF4 is associated with hereditary cataract in the Australian Shepherd. Veterinary Ophthalmology, 2009; 12:372-8.

Mellersh CS, Pettitt L, Forman OP, Vaudin M, Barnett KC. Identification of mutations in HSF4 in dogs of three different breeds with hereditary cataracts. Veterinary Ophthalmology, 2006; 9:369-78.

Progressive retinal atrophy (PRA) refers to a group of diseases that cause the retina of the eye to degenerate slowly over time. The result is declining vision and eventual blindness. The dominant form of PRA is found in Mastiffs and Bullmastiffs. The genetic mutation that causes dominant PRA was found by researchers at Cornell University. The mutation is in the rhodopsin (RHO) gene which is located on canine chromosome 20. Rhodopsin is the G protein-coupled receptor that is activated by light and initiates the transduction cascade leading to night (rod) vision. Dogs with this mutant allele have a dramatically slowed time course of recovery of rod photoreceptor function after light exposure and retinal degeneration that can lead to blindness. Typically, the clinical disease is first recognized during eye examinations in adolescence or early adulthood, but changes may not be visible until later.

Dominant PRA is a dominantly inherited disorder meaning that dogs only need to inherit one copy of the mutated RHO gene to be at risk of developing the clinical signs. To date, the dominant PRA mutation has been identified in Mastiffs, Bullmastiffs, and crosses of these breeds.

Mixed-breed dogs that have inherited one copy of this mutation can also develop dominant PRA. Educating clients with dogs who are susceptible to dominant PRA is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on PRA and testing for the dominant PRA mutation:
http://www.optigen.com/opt9_test_dominant_pra.html

References:
Kijas JW, Cideciyan AV, Aleman TS, Pianta MJ, Pearce-Kelling SE, Miller BJ, Jacobson SG, Aguirre GD, Acland GM. Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6328-33.

Kijas JW, Miller BJ, Pearce-Kelling SE, Aguirre GD, Acland GM. Canine models of ocular disease: outcross breedings define a dominant disorder present in the English mastiff and bull mastiff dog breeds. J Hered. 2003 Jan-Feb;94(1):27-30.

Early-onset hereditary cataracts occur bilaterally and can be diagnosed as early as 8-12 weeks of age, but they are not congenital. The cataracts become obvious at 9-15 months of age with further progression and maturity between 2-4 years. The genetic mutation that causes early-onset hereditary cataracts was identified by researchers at the Animal Health Trust and is a single base pair insertion that disrupts the correct translation of the HSF4 gene. The HSF4 gene is located on canine chromosome 5. Note that another mutation in HSF4 has been associated with a dominant form of cataracts in the Australian Shepherd.

Early-onset hereditary cataracts is a recessive disorder meaning that dogs must inherit two copies of the mutated HSF4 gene to be at risk of developing the clinical signs. To date, the early-onset cataract mutation in HSF4 has been identified in Boston Terriers, Staffordshire Bull Terriers and the French Bulldog.

Mixed-breed dogs that have inherited two copies of this mutation can also develop early onset cataracts. Educating clients with dogs who are susceptible to early-onset cataracts is important so they can recognize the clinical signs and care for their dogs.

For more information on early-onset cataracts and testing for the HSF4 mutation:
http://www.aht.org.uk/genetics_jhccataracts.html

References:
Mellersh CS, Graves KT, McLaughlin B, Ennis RB, Pettitt L, Vaudin M, Barnett KC. Mutation in HSF4 associated with early but not late-onset hereditary cataract in the Boston Terrier. Journal of Heredity, 2007; 98:531-3.

Mellersh CS, Pettitt L, Forman OP, Vaudin M, Barnett KC. Identification of mutations in HSF4 in dogs of three different breeds with hereditary cataracts. Veterinary Ophthalmology, 2006; 9:369-78.

Exercise-induced collapse (EIC) is an inherited condition in dogs that causes them to have muscle weakness, uncoordinated gate, and collapse after approximately 5-20 minutes of strenuous exercise. The collapse event usually lasts for 5-10 minutes with complete recovery after approximately 30 minutes, however, occasionally these episodes are fatal. The genetic mutation that causes EIC was recently discovered by researchers at the University of Minnesota. The mutation is in the dynamin 1 (DNM1) gene which is located on canine chromosome 9. The mutation disrupts dynamin protein’s ability to release endocytic synaptic vesicles in the brain and spinal cord which are vital for neurotransmitter communication between cells.

EIC is a recessive disorder meaning that dogs must inherit two copies of the mutated DNM1 gene to be at risk of developing the clinical signs. To date, the DNM1 mutation causing EIC has been identified in Labrador Retrievers, Curly-Coated Retrievers, and Chesapeake Bay Retrievers. It has been estimated that 40% of the Labrador Retrievers in the United States carry one or two copies of the DNM1 mutation.

Mixed-breed dogs that have inherited two copies of this DNM1 mutation can also develop EIC. Educating clients with dogs who are susceptible to EIC is very important to avoid a collapsing event or appropriately treat such an event. It is equally important to definitively diagnosis or rule-out EIC in a dog that has had a collapsing event.

For more information on EIC and testing for the EIC mutation:
http://www.cvm.umn.edu/vdl/ourservices/canineneuromuscular/home.html

References:
Patterson EE, Minor KM, Tchernatynskaia AV, Taylor SM, Shelton GD, Ekenstedt KJ, Mickelson JR. A canine dynamin 1 mutation is highly associated with the syndrome of exercise-induced collapse. Nature Genetics 2008; 40(10): 1235-1239

Taylor SM, Shmon CL, Adams VJ, Mickelson JR, Patterson EE, Shelton GD. Evaluations of Labrador Retrievers with Exercise Induced Collapse, including response to a standardized strenuous exercise protocol. Journal of the American Animal Hospital Association, January 2009.

Taylor SM, Shmon CL, Shelton GD, Patterson EE, Minor K, Mickelson JR. Exercise Induced Collapse of Labrador Retrievers: Survey results and preliminary investigation of heritability. Journal of the American Animal Hospital Association, November 2008; 44: 295-301.

Taylor SM. Exercise-induced Weakness/Collapse in Labrador Retrievers In LP Tilley and FW Smith (eds), 2008, Blackwell's Five Minute Veterinary Consult: Canine and Feline (4 th edition). 458-459.

Familial nephropathy (FN) causes a juvenile-onset, fatal renal failure in English Cocker Spaniels. While FN renal failure is invariably progressive and ultimately fatal, the rate of disease progression observed in affected dogs is more rapid in some individuals than in others. Dogs with FN typically develop chronic renal failure between 6 months and 2 years of age, with eventual and sometimes rapid destruction of both kidneys. The early clinical signs are the same as those associated with chronic renal failure due to any other cause (e.g. excessive water consumption, excessive urine volume, reduced growth rate or weight loss, poor quality hair coat, reduced appetite, and vomiting). Persistent high levels of protein in the urine of a young English Cocker Spaniel most often proves to be due to FN. The genetic mutation that causes FN in the English Cocker Spaniel was identified by researchers at Texas A&M University. The mutation is in the COL4A4 collagen gene located on canine chromosome 25.

FN is a recessively inherited disorder meaning that dogs must inherit two copies of the mutated COL4A gene to be at risk of developing the clinical signs. To date, the COL4A4 mutation has been identified in the English Cocker Spaniel.

Mixed-breed dogs that have inherited two copies of this mutation can also develop FN. Educating clients with dogs who are susceptible to FN is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on FN and testing for the COL4A4 mutation:
http://www.optigen.com/opt9_ecsfn1215ann.html

References:
Davidson AG, Bell RJ, Lees GE, Kashtan CE, Davidson GS, Murphy KE. Genetic cause of autosomal recessive hereditary nephropathy in the English Cocker Spaniel. J Vet Intern Med. 2007 May-Jun;21(3):394-401.

Multi-drug sensitivity, also known as ivermectin sensitivity, is an inherited condition in dogs that causes them to have enhanced sensitivity to certain drugs resulting in adverse signs of neurotoxicity. The clinical signs of toxicity in susceptible dogs depend on the administered drug and its concentration and can range from more mild cases of salivation, disorientation, and ataxia to severe cases with coma and potentially death of the dog. Affected dogs may require days or weeks of supportive care until they recover. The genetic mutation that causes multi-drug sensitivity was found by researchers at Washington State University. The mutation is in the multi-drug resistance (MDR1) gene (also known as ABCB1) which is located on canine chromosome 14. The MDR1 gene encodes for a P-glycoprotein that is located in the blood-brain barrier and is responsible for pumping many drugs and toxins across the barrier and out of the brain. The multi-drug sensitivity mutation results in a severely shortened MDR1 protein that renders the pump non-functional. Drugs that can cause adverse effects in dogs with this MDR1 mutation include ivermectin, loperamide, acepromazine, butorphanol, erythromycin, selamectin, milbemycin, moxidectin, vincristine, vinblastine, and doxorubicin.

Multidrug sensitivity is a dominant disorder meaning that dogs that inherit one or two copies of the MDR1 mutation can show clinical signs of neurotoxicity. To date, the MDR1 mutation causing multi-drug sensitivity has been identified world-wide in a wide range of breeds including the Collie, Australian Shepherd, Shetland Sheepdog, Old English Sheepdog, Border Collie, Long-haired Whippet, and German Shepherd. It has been estimated that that the allele frequency for this MDR1 mutation is 70% in Collies and 50% in Australian Shepherds in the United States.

Mixed-breed dogs that have inherited at least one copy of this MDR1 mutation can also develop neurotoxicity if treated with a problem drug. Cautiously medicating dogs that have this MDR1 mutation and educating their owners are very important to avoid costly and potentially lethal adverse events.

For more information on multi-drug sensitivity and testing for the MDR1 mutation:
http://www.vetmed.wsu.edu/depts-vcpl/

References:
Mealey KL, Bentjen SA, Gay J, Cantor GH. Ivermectin sensitivity in Collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics, 2001;11:727-733.

Nelson OL, Carsten E, Bentjen SA, Mealey, KL. Ivermectin toxicity in an Australian Shepherd dog with the MDR1 mutation associated with ivermectin sensitivity in Collies, Journal of Veterinary Internal Medicine, 2003;17:354-356.

Mealey KL, Bentjen SA, Waiting D. Frequency of the mutant MDR1 allele associated with ivermectin sensitivity in a sample population of Collies from the northwestern United States. American Journal of Veterinary Research, 2002;63:479-481.

Mealey KL, Northrop NC, Bentjen SA. Increased susceptibility to P-glycoprotein substrate chemotherapeutic agents in a Collie with the MDR1 deletion mutation associated with ivermectin sensitivity, Journal of the American Veterinary Medical Association, 2003;223:1453-1455.

Neff MW, Robertson KR, Wong A, Safra N, Broman KW, Slatkin M, Mealey KL, Pedersen NC. Breed distribution and history of canine mdr1-1d, a pharmacogenetic mutation that marks the emergence of breeds of the collie lineage. Proceedings of the National Academy of Sciences , 2004; 101:11725-11730.

Sartor LL, Bentjen SA, Trepanier L, Mealey KL. Loperamide toxicity after therapeutic doses in a Collie with the MDR1 mutation associated with ivermectin sensitivity. Journal of Veterinary Internal Medicine, 2004;18:117-118.

Mealey KL, Meurs KM. Breed Distribution and Frequency of the ABCB1-1D (Multidrug Sensitivity) Polymorphism in Dogs; J Am Vet Med Assoc, 2008;233:921-924.

Musladin-Lueke syndrome (MLS) is an inherited disorder in Beagles that affects the development and structure of connective tissue. It is characterized by stiff joints, extensive fibrosis of the skin, which makes the skin very thick and taut, and short stature. Affected Beagles also have a broad skull with wide-set slanted eyes, creased ears, a hopping gait, and short outer digits. The genetic mutation that causes MLS was identified by researchers at the Cleveland Clinic and the University of California, Davis. It is due to a single base pair mutation in exon 7 of the ADAMTSL2 gene, which is involved in regulation of tissue fibrosis. This mutation changes the structure of ADAMTSL2 making it non-functional. This affects ADAMTSL2’s ability to properly regulate TGFβ, resulting in increased tissue fibrosis. The ADAMTSL2 gene is located on canine chromosome 9.

MLS is a recessively inherited disorder, meaning that dogs must inherit two copies of the mutated ADAMTSL2 gene to be at risk of developing the clinical signs. However, dogs with only one copy of the mutation may demonstrate more subtle clinical signs that do not appear to cause health-related defects. To date, the ADAMTSL2 mutation has been identified exclusively in Beagles.

Mixed-breed dogs that have inherited two copies of this mutation can also develop MLS. Educating clients with dogs who are susceptible to MLS is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on MLS and testing for the ADAMTSL2 mutation:
http://www.vgl.ucdavis.edu/services/MLS.php

References:
Bader HL, Ruhe AL, Wang LW, Wong AK, Walsh KF, Packer RA, Mitelman J, Robertson KR, O'Brien DP, Broman KW, Shelton GD, Apte SS, Neff MW. An ADAMTSL2 founder mutation causes Musladin-Lueke Syndrome, a heritable disorder of beagle dogs, featuring stiff skin and joint contractures. PLoS One, 2010; 5(9).

Narcolepsy is a debilitating sleep disorder. In dogs, it is characterized by sudden episodes of muscle weakness and apparent periods of sleep. These episodes are often triggered by excitement and positive emotions which can be due to the presentation of food, toys, or other enjoyable activities. The genetic mutations that cause narcolepsy were identified by researchers at Stanford University. The mutations are in the hypocretin (orexin) receptor 2 gene (Hcrtr2) located on canine chromosome 12. Canine narcolepsy was extensively studied as a model of the human condition. These Hcrtr2 mutations found in the dogs lead researchers to examine this pathway further where they identified a number of other genes responsible for many cases of human narcolepsy.

Narcolepsy is a recessively inherited disorder meaning that dogs must inherit two copies of the mutated Hcrtr2 gene to be at risk of developing the clinical signs. To date, the Hcrtr2 mutation has been identified in the Doberman Pinscher, Dachshund, and Labrador Retriever.

Mixed-breed dogs that have inherited two copies of this mutation can also develop narcolepsy. Educating clients with dogs who are susceptible to narcolepsy is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on narcolepsy and testing for the Hcrtr2 mutation:
http://www.optigen.com/opt9_test_narc.html

References:
Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999 Aug 6;98(3):365-76.

Hungs M, Fan J, Lin L, Lin X, Maki RA, Mignot E. Identification and functional analysis of mutations in the hypocretin (orexin) genes of narcoleptic canines. Genome Res. 2001 Apr;11(4):531-9.

Neuronal ceroid lipofucinosises (NCLs) are inherited lysosomal storage diseases that cause progressive neurodegeneration in a number of dog breeds and is characterized by accumulation of autofluorescent cytoplasmic antibodies within cells of the nervous system. NCL signs can include disorientation, ataxia, weakness, visual impairment, and behavioral changes. Dachshunds can develop an early onset form of NCL due to a mutation in the palmitoyl protein thioesterase 1 (PPT1) gene. This mutation was identified by researchers at the University of Missouri and is located on canine chromosome 15. Mutations in the PPT1 gene have also been associated with NCL in humans.

NCL is a recessive disorder meaning that dogs must inherit two copies of the mutated PPT1 gene to be at risk of developing the clinical signs. To date, the PPT1 mutation has been identified in the Dachshund.

Mixed-breed dogs that have inherited two copies of this mutation can also develop NCL. Educating clients with dogs who are susceptible to NCL is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on NCL and testing for the PPT1 mutation:
http://www.caninegeneticdiseases.net/DNAtests/TESTSnow.htm

References:
Sanders DN, Farias FH, Johnson GS, Chiang V, Cook JR, O'Brien DP, Hofmann SL, Lu JY, Katz ML A mutation in canine PPT1 causes early onset neuronal ceroid lipofuscinosis in a Dachshund. Molecular Genetics and Metabolism, 2010; 100:349-56.

Neuronal ceroid lipofucinosises (NCLs) are inherited lysosomal storage diseases that cause progressive neurodegeneration in a number of dog breeds and is characterized by accumulation of autofluorescent cytoplasmic antibodies within cells of the nervous system. American Bulldogs and English Setters can develop a young-adult onset NCL due to a mutation in the cathepsin D (CSTD) gene. This mutation was identified by researchers at the University of Missouri and is located on canine chromosome 21.

NCL is a recessive disorder meaning that dogs must inherit two copies of the mutated CSTD gene to be at risk of developing the clinical signs. To date, the CSTD mutation has been identified in American Bulldogs and English Setters.

Mixed-breed dogs that have inherited two copies of this mutation can also develop NCL. Educating clients with dogs who are susceptible to NCL is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on NCL and testing for the CSTD mutation:
http://www.vetgen.com/canine-NCL.html

References:
Awano T, Katz ML, O'Brien DP, Taylor JF, Evans J, Khan S, Sohar I, Lobel P, Johnson GS. A mutation in the cathepsin D gene (CTSD) in American Bulldogs with neuronal ceroid lipofuscinosis.

Progressive retinal atrophy (PRA) refers to a group of diseases that cause the retina of the eye to degenerate slowly over time. The result is declining vision and eventual blindness. Progressive rod-cone degeneration (prcd) is an inherited form of PRA found in several breeds. Prcd-PRA, causes cells in the retina at the back of the eye to degenerate and die, even though the cells seem to develop normally early in life. The "rod" cells operate in low light levels and are the first to lose normal function resulting in night blindness. Then the "cone" cells gradually lose their normal function in full light situations. Most affected dogs will eventually be blind. Typically, the clinical disease is recognized first in early adolescence or early adulthood. The genetic mutation that causes prcd-PRA was found by researchers at Cornell University. The mutation is in the "progressive rod-cone degeneration" (PRCD) gene which is located on canine chromosome 9.

Prcd-PRA is a recessive disorder meaning that dogs must inherit two copies of the mutated PRCD gene to be at risk of developing the clinical signs. To date, the PRCD mutation has been identified in a number of breeds including the American Cocker Spaniel, American Eskimo Dog, Australian Cattle Dog, Australian Shepherd, Chesapeake Bay Retrievers, Chinese Crested, English Cocker Spaniel, Golden Retriever, Kuvasz, Labrador Retriever, Miniature and Toy Poodle, Norwegian Elkhound, Nova Scotia Duck Tolling Retriever, Portuguese Water Dog, Silky Terrier, and Yorkshire Terrier.

Mixed-breed dogs that have inherited two copies of this mutation can also develop prcd-PRA. Educating clients with dogs who are susceptible to prcd-PRA is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on PRA and testing for the prcd-PRA mutation:
http://www.optigen.com/opt9_test_prcd_pra.html

References:
Zangerl B, Goldstein O, Philp AR, Lindauer SJ, Pearce-Kelling SE, Mullins RF, Graphodatsky AS, Ripoll D, Felix JS, Stone EM, Acland GM, Aguirre GD. Identical mutation in a novel retinal gene causes progressive rod-cone degeneration in dogs and retinitis pigmentosa in humans. Genomics. 2006 Nov;88(5):551-63.

Gu W, Acland GM, Langston AA, Ostrander EA, Aguirre GD, Ray K. Identification of a RAPD marker linked to progressive rod-cone degeneration in dogs. Mamm Genome. 1998 Sep;9(9):740-4.

Acland GM, Ray K, Mellersh CS, Gu W, Langston AA, Rine J, Ostrander EA, Aguirre GD. Linkage analysis and comparative mapping of canine progressive rod-cone degeneration (prcd) establishes potential locus homology with retinitis pigmentosa (RP17) in humans. Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3048-53.

Recent research at the University of Toronto has led to the identification of a mutation in the canine pyruvate dehydrogenase phosphatase I (PDP1) gene on canine chromosome 29. This mutation leads to a deficit in the enzyme which is involved in activation of the pyruvate dehydrogenase complex in cellular metabolism. To date, the PDP1 mutation has been identified in Clumber Spaniels and Sussex Spaniels. Over 20% of each breed population is estimated to be a carrier for the mutant form of the PDP1 gene. Dogs carrying two copies of the null mutation have profound exercise intolerance due to the deficit of PDP1 enzyme and may collapse after exercising for brief periods.

PDP1 is a recessive disorder meaning that dogs must inherit two copies of the mutated PDP1 gene to be at risk of developing the clinical signs. Mixed-breed dogs that have inherited two copies of this mutation can also develop PDP1. Educating clients with dogs who are susceptible to PDP1 is important so they can recognize the clinical signs and care for their dogs appropriately including potential dietary treatments.

For more information on PDP1 and testing for the mutation:
http://www.vetgen.com/canine-pdp1.html
http://www.aht.org.uk/genetics_pdp1.html

References:
Cameron JM, Maj MC, Levandovskiy V, MacKay N, Shelton GD, Robinson BH. Identification of a canine model of pyruvate dehydrogenase phosphatase 1 deficiency. Molecular Genetics and Metabolism, 2007; 90:15-23.

Abramson,C.J., Platt,S.R. and Shelton,G.D. Pyruvate dehydrogenase deficiency in a Sussex spaniel. Journal of Small Animal Practice, 2004; 45:162-165

Renal cystadenocarcinoma nodular dermatofibrosis (RCND) is an inherited condition in dogs that can cause renal cancer. Clinical characteristics of RCND include bilateral, multifocal tumors in the kidneys, uterine leiomyomas, and skin nodules consisting of dense collagen fibers; ~50% of the dogs experience metastasis. The genetic mutation that causes RCND was identified by researchers at the Norwegian School of Veterinary Science in Oslo, Norway. The mutation is in a gene that has been previously associated with a human renal cancer syndrome called Birt-Hogg-Dube (BHD). The BHD gene is located on canine chromosome 5. The BHD gene encodes for the protein folliculin, however its function is not fully understood at this time.

RCND is a dominant disorder meaning that dogs that inherit one copy of the BHD mutation will develop RCND. There is evidence that the RCND mutation may have a homozygous lethal effect, meaning dogs that inherit two copies of the BHD mutation do not survive. To date, the RCND mutation has been identified in German Shepherd dogs.

Mixed-breed dogs that have inherited one copy of the BHD mutation can also develop RCND. Educating clients with dogs who are susceptible to RCND is important so they can recognize the clinical signs and care for their dogs appropriately.

For more information on RCND and testing for the BHD mutation:
http://www.vetgen.com/canine-rcnd.html

References:
Lingaas F, Comstock KE, Kirkness EF, Sørensen A, Aarskaug T, Hitte C, Nickerson ML, Moe L, Schmidt LS, Thomas R, Breen M, Galibert F, Zbar B, Ostrander EA. A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. Human Molecular Genetics, 2003; 12:3043-53.

Jónasdóttir TJ, Mellersh CS, Moe L, Heggebø R, Gamlem H, Ostrander EA, Lingaas F. Genetic mapping of a naturally occurring hereditary renal cancer syndrome in dogs. Proceedings of the National Academy of Science USA, 2000; 97:4132-7.

Retinal dysplasia (RD) causes retinal folds which are a common clinical observation in many dog breeds. Since many retinal folds are benign and of unknown heritability, veterinary ophthalmologists will often advise that breeding dogs with RD is an acceptable option. However in two breeds, the Labrador Retriever and the Samoyed, RD is of much greater concern as they are linked to a condition called oculo-skeletal dysplasia (OSD). OSD is a severe condition in which the dogs show a variety of skeletal malformations, including shortened limbs (dwarfism), and blindness at an early age; the blindness results from a generalized malformation of the retina that causes a partial or full retinal detachment and cataracts. The genetic mutations that cause RD/OSD in Labrador Retrievers and Samoyed were recently found by researchers at Cornell University.

RD/OSD is a semi-dominantly inherited disorder meaning that dogs that inherit one copy of the RD/OSD mutation display RD with benign retinal folds, however, dogs that inherit two copies of the RD/OSD mutation to be affected with OSD. To date, two RD/OSD mutations have been identified in the Labrador Retriever and Samoyed.

Mixed-breed dogs that have inherited this mutation can also develop RD and OSD. Educating clients with dog