Association of MITF with white spotting in Beagle crosses and Newfoundland dogs.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
N M Ellinwood
Publications and source records attributed to N M Ellinwood.
Gene therapy ameliorates cardiovascular disease in dogs with mucopolysaccharidosis VII.
BACKGROUND: Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient beta-glucuronidase (GUSB) activity resulting in defective catabolism of glycosaminoglycans (GAGs). Cardiac disease is a major cause of death in MPS VII because of accumulation of GAGs in cardiovascular cells. Manifestations include cardiomyopathy, mitral and aortic valve thickening, and aortic root dilation and may cause death in the early months of life or may be compatible with a fairly normal lifespan. We previously reported that neonatal administration of a retroviral vector (RV) resulted in transduction of hepatocytes, which secreted GUSB into the blood and could be taken up by cells throughout the body. The goal of this study was to evaluate the effect on cardiac disease. METHODS AND RESULTS: Six MPS VII dogs were treated intravenously with an RV-expressing canine GUSB. Echocardiographic parameters, cardiovascular lesions, and biochemical parameters of these dogs were compared with those of normal and untreated MPS VII dogs. CONCLUSIONS: RV-treated dogs were markedly improved compared with untreated MPS VII dogs. Most RV-treated MPS VII dogs had mild or moderate mitral regurgitation at 4 to 5 months after birth, which improved or disappeared when evaluated at 9 to 11 and at 24 months. Similarly, mitral valve thickening present early in some animals disappeared over time, whereas aortic dilation and aortic valve thickening were absent at all times. Both myocardium and aorta had significant levels of GUSB and reduction in GAGs.
Animals↗
A model of mucopolysaccharidosis IIIB (Sanfilippo syndrome type IIIB): N-acetyl-alpha-D-glucosaminidase deficiency in Schipperke dogs.
Mucopolysaccharidosis III (MPS III) is characterized by lysosomal accumulation of the glycosaminoglycan (GAG) heparan sulphate (HS). In humans, the disease manifests in early childhood, and is characterized by a progressive central neuropathy leading to death in the second decade. This disease has also been described in mice (MPS IIIA and IIIB), dogs (MPS IIIA), emus (MPS IIIB) and goats (MPS IIID). We now report on dogs with naturally occurring MPS IIIB, detailing the clinical signs, diagnosis, histopathology, tissue enzymology and substrate levels. Two 3-year-old Schipperke dogs were evaluated for tremors and episodes of stumbling. Examination of the animals found signs consistent with cerebellar disease including dysmetria, hind limb ataxia and a wide-based stance with truncal swaying. There were mildly dystrophic corneas and small peripheral foci of retinal degeneration. Magnetic resonance imaging of the brain and skeletal radiographs were normal. Intracytoplasmic granules were found in the white cells of peripheral blood and cerebral spinal fluid, and in myeloid lineages in bone marrow. Electrophoresis of urinary GAGs indicated the presence of HS, while assays of cultured fibroblasts found N-acetyl-alpha-D-glucosaminidase (Naglu) activity of between 4.3% and 9.2% of normal. Owing to neurological deterioration, both dogs were euthanized, and post-mortem examinations were performed. Biochemical studies of liver and kidney from both animals demonstrated profound deficiency of Naglu activity and abnormally high GAG levels. Pathology of the brain included severe cerebellar atrophy, Purkinje cell loss, and cytoplasmic vacuolation in neurons and perithelial cells throughout the central nervous system. Pedigree analyses and Naglu levels of family members supported an autosomal recessive mode of inheritance. Using an obligate heterozygote, a breeding colony has been established to aid in understanding the pathogenesis of MPS IIIB and testing of potential therapies.
Acetylglucosaminidase↗
Animal models for mucopolysaccharidoses and their clinical relevance.
The mucopolysaccharidoses (MPS) are characterized by the accumulation of glycosaminoglycans (GAG) and result from the impaired function of one of 11 enzymes required for normal GAG degradation. MPS II was the first MPS to be defined clinically in humans and is caused by deficient activity of the enzyme iduronate-2-sulphatase. MPS VI was the first MPS recognized in an animal; since then, all but MPS IIIC and IX have been described as naturally occurring in animals or made by knock-out technology. As in humans, all are inherited as autosomal recessive traits, except for MPS II, which is X-linked. Most animal colonies have been established from single related heterozygous animals, making the affected offspring homozygous for the same mutant allele. Importantly, these models have disease pathology that is similar to that seen in humans, making the animals extremely valuable for the investigation of disease pathogenesis and the testing of therapies. Large animal homologues are similar to humans in natural genetic diversity, approaches to therapy and care, and the possibility of evaluating long-term effects of treatment. Therapeutic strategies for MPS include enzyme replacement therapy, heterologous bone marrow transplantation, and somatic cell gene transfer, all of which have been tested in animals with some success.
Animals↗
MX1 maps to cattle chromosome 1.
Explore the source record for details and available documents.
Alleles↗
Cloning and characterization of cDNAs for a bovine (Bos taurus) Mx protein.
Mx proteins are GTPases that are stringently induced in cells from many vertebrates on exposure to type I interferons (IFNs), and expression of some Mx proteins potently inhibits replication of specific viruses. Two cDNAs encoding bovine Mx proteins were isolated from an endometrial phage library. The open reading frames (ORFs) of these two clones predict proteins of 654 (Mxl) and 648 (Mxl-a) residues. Both possess the tripartite GTPase domains, dynamin signature, and leucine zipper motifs conserved in all other Mx proteins identified. The bovine protein sequences show highest identity to ovine Mx (93%) and are substantially similar to human MxA (73%) and mouse Mx1 (63%). Based on differences between the two bovine clones in the coding and 3'-untranslated regions, it was concluded that they represent two alleles of one gene, and heterozygous and homozygous cattle were identified. Expression of Mx mRNA was rapidly induced in cultured bovine cells by treatment with IFN.
Amino Acid Sequence↗
MC1R studies in dogs with melanistic mask or brindle patterns.
Black mask is a characteristic pattern in which red, yellow, tan, fawn, or brindle dogs exhibit a melanistic muzzle which may extend up onto the ears. Melanistic mask is inherited in several breeds as an autosomal dominant trait, and appears to be a fixed trait in a few breeds of dogs. A MC1R nonsense mutation, R306ter, has been shown to cause a completely red or yellow coat color in certain breeds such as Irish setters, yellow Labrador retrievers, and golden retrievers. The amino acid sequence for the melanocortin receptor 1 gene (MC1R) was examined in 17 dogs with melanistic masks from seven breeds, 19 dogs without melanistic masks, and 7 dogs in which their coat color made the mask difficult to distinguish. We also examined nine brindle dogs of four breeds, including three dogs who also had a black mask. No consistent amino acid change was observed in the brindle dogs. All dogs with a melanistic mask had at least one copy of a valine substitution for methionine at amino acid 264 (M264V) and none were homozygous for the premature stop codon (R306ter). These results suggest that black mask, but not brindle, is caused by a specific MC1R allele.
Amino Acid Substitution↗
Deficiency of fucosidase results in acrosomal dysgenesis and impaired sperm maturation.
Although a variety of glycosyltransferases and glycosidases have been implicated in spermatogenesis and posttesticular sperm maturation, the biological role of these enzymes in these processes is largely unknown. We describe reproductive sequelae in a cohort of male dogs suffering from fucosidosis, a heritable lysosomal storage disorder caused by a severe deficiency of alpha-L-fucosidase. There was a reduction in the total number of sperm in the ejaculate. Only 3-5% of sperm were motile. None of the sperm were found to be morphologically normal. The predominant morphological defects observed were malformed acrosomes (56%) and retained proximal cytoplasmic droplets (92%), indicating that spermiogenesis and sperm maturation were impaired. The cytoplasm of all cellular components of the testis and excurrent ducts were vacuolated. The vacuolation resulted from enlargement of lysosomes caused by accumulation of compounds that are otherwise cleaved/degraded when lysosomal hydrolases are present normally. It is possible that impairment in spermatogenesis, particularly morphogenesis of the acrosome, is due to physical damage caused by anomalous enlargement of lysosomes. Although an unambiguous causal relationship could not be established, it is evident from the available information that the derangement in events associated with epididymal sperm maturation, namely acquisition of motility and shedding of the cytoplasmic droplet, is likely due to lack of fucosidase leading to impaired sperm membrane modification. This heritable condition in dogs may serve as a spontaneously occurring knock-out model for further elucidating the role of alpha-L-fucosidase in spermatogenesis and sperm maturation.
Acrosome↗