Post by David Feder on Jul 29, 2008 22:20:35 GMT -5
Ringo, a Golden Retriever Muscular Dystrophy (GRMD) dog with absent dystrophin but normal strength
C.E. Ambrósioa, M.C. Valadaresb, E. Zucconib, R. Cabrala, P.L. Pearsonb, T.P. Gaiada, M. Canovasb, M. Vainzofb, M.A. Miglinoa, b and M. Zatzb, Corresponding Author Contact Information, E-mail aSchool of Veterinary Medicine and Animal Science, Department of Surgery, Anatomy Sector, University of São Paulo, São Paulo, Brazil
bHuman Genome Research Center, Biosciences Institute, IB-USP, University of São Paulo, R. do Matão, 106, São Paulo, SP-CEP 05508-090, Brazil
The closest model to human Duchenne Muscular Dystrophy (DMD) is the Golden Retriever Muscular Dystrophy (GRMD) dog, which carries a point mutation in the splice acceptor site in intron 6 of the orthologe X-linked dystrophin gene, leading to the absence of protein in the muscles. These dogs present clinical signs within the first weeks of life involving the limbs as well as masticatory muscles. Diaphragmatic and intercostal muscles impairment leads to progressive respiratory failure. Death occurs from bronchopneumonia and cardiac arrest, usually before 2 years of age.
Here, we report the case of Ringo, an exceptional GRMD dog showing an unusually mild course. Currently, at age 4 years and 10 months he is able to run, jump and open doors while standing on his rear paws. He was also able to breed naturally, which apparently has never been reported before.
Ringo’s performance has apparently never been observed in GRMD dogs. Although their phenotype may be highly variable, even among dogs from the same litter, most of the GRMD dogs are severely affected and die before 24 months of age. In the Brazilian colony, we observed that 24% died within the first 2 weeks, 17% died before 6 months, 24% before 12 months, 11% before 18 months and 24% after 24 months of age.
Interestingly, histopathological and immunohistochemistry analysis from Ringo’s biceps biopsy showed typical features of a dystrophic process with variability in fiber size, splitting, degeneration and connective tissue as well as complete dystrophin deficiency, comparable to severely affected GRMD dogs (with both rod- and C-terminal anti-dystrophin antibodies). Sarcoglycans were partially deficient, and utrophin was overexpressed, in a pattern similar to the observed in severely affected dogs.
How much dystrophin is required in order to mitigate the clinical phenotype has always been an open question. Ringo’s phenotype, which is not explained by higher amounts of dystrophin or up-regulation of utrophin, shows that GRMD dogs may have a mild course despite the complete absence of dystrophin, which opens a new avenue of investigations. On the other hand this observation reinforces the importance of taking into account clinical variability in the assessment of results of therapeutic trials that are currently underway. What is protecting Ringo and Suflair from the mitigating effect of the dystrophin mutation? The observed father to son transmission rules out X-linked inheritance and therefore this unusual phenotype could be due to modifier genes, to multifactorial inheritance or to other epigenetic factors. Complete absence of dystrophin expression associated with a mild clinical course has been recently reported in humans (Neuromuscul Disord 2006;16:865–6). “Treasure your exceptions”, says Victor Dubowitz. Maybe Ringo and his descendants could enhance our comprehension on unknown mechanisms that might protect skeletal muscle to degenerate despite the absence of dystrophin.
C.E. Ambrósioa, M.C. Valadaresb, E. Zucconib, R. Cabrala, P.L. Pearsonb, T.P. Gaiada, M. Canovasb, M. Vainzofb, M.A. Miglinoa, b and M. Zatzb, Corresponding Author Contact Information, E-mail aSchool of Veterinary Medicine and Animal Science, Department of Surgery, Anatomy Sector, University of São Paulo, São Paulo, Brazil
bHuman Genome Research Center, Biosciences Institute, IB-USP, University of São Paulo, R. do Matão, 106, São Paulo, SP-CEP 05508-090, Brazil
The closest model to human Duchenne Muscular Dystrophy (DMD) is the Golden Retriever Muscular Dystrophy (GRMD) dog, which carries a point mutation in the splice acceptor site in intron 6 of the orthologe X-linked dystrophin gene, leading to the absence of protein in the muscles. These dogs present clinical signs within the first weeks of life involving the limbs as well as masticatory muscles. Diaphragmatic and intercostal muscles impairment leads to progressive respiratory failure. Death occurs from bronchopneumonia and cardiac arrest, usually before 2 years of age.
Here, we report the case of Ringo, an exceptional GRMD dog showing an unusually mild course. Currently, at age 4 years and 10 months he is able to run, jump and open doors while standing on his rear paws. He was also able to breed naturally, which apparently has never been reported before.
Ringo’s performance has apparently never been observed in GRMD dogs. Although their phenotype may be highly variable, even among dogs from the same litter, most of the GRMD dogs are severely affected and die before 24 months of age. In the Brazilian colony, we observed that 24% died within the first 2 weeks, 17% died before 6 months, 24% before 12 months, 11% before 18 months and 24% after 24 months of age.
Interestingly, histopathological and immunohistochemistry analysis from Ringo’s biceps biopsy showed typical features of a dystrophic process with variability in fiber size, splitting, degeneration and connective tissue as well as complete dystrophin deficiency, comparable to severely affected GRMD dogs (with both rod- and C-terminal anti-dystrophin antibodies). Sarcoglycans were partially deficient, and utrophin was overexpressed, in a pattern similar to the observed in severely affected dogs.
How much dystrophin is required in order to mitigate the clinical phenotype has always been an open question. Ringo’s phenotype, which is not explained by higher amounts of dystrophin or up-regulation of utrophin, shows that GRMD dogs may have a mild course despite the complete absence of dystrophin, which opens a new avenue of investigations. On the other hand this observation reinforces the importance of taking into account clinical variability in the assessment of results of therapeutic trials that are currently underway. What is protecting Ringo and Suflair from the mitigating effect of the dystrophin mutation? The observed father to son transmission rules out X-linked inheritance and therefore this unusual phenotype could be due to modifier genes, to multifactorial inheritance or to other epigenetic factors. Complete absence of dystrophin expression associated with a mild clinical course has been recently reported in humans (Neuromuscul Disord 2006;16:865–6). “Treasure your exceptions”, says Victor Dubowitz. Maybe Ringo and his descendants could enhance our comprehension on unknown mechanisms that might protect skeletal muscle to degenerate despite the absence of dystrophin.
