Defects in collagen fibrillogenesis causing hyperextensible, fragile skin in dogs.
ABSTRACT Two unrelated mixed-breed dogs were donated for studies of their fragile, hyperextensible skin. Breeding of these dogs to bitches with normal skin showed that half of their male and female offspring also had fragile, hyperextensible skin, indicating that the defect was transmitted as an autosomal dominant trait in both dogs. Electron microscopy showed distinct abnormalities in the packing of collagen into fibrils and fibers in affected skin. These packing defects in dermal collagen were identical in related dogs, but were slightly different in unrelated animals. A clinical test, the skin extensibility index, was used to quantitate the extensibility of affected and unaffected skin. This index ranged from 8% to 15% in normal dogs and from 17% to 25% in newborn pups and adult dogs with collagen packing defects. The tensile strength of dorsolateral thoracic skin of affected pups was only 5% to 10% of that of matched specimens of paired littermates. The hyperextensibility and fragility of skin were the only clinical signs, but radiographic and microradiographic studies revealed subclinical involvement of bone.
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ABSTRACT: A defect of the core protein of dermatan sulfate proteoglycan was suspected in a Holstein calf affected with a variant form of Ehlers-Danlos syndrome. The mutation was a guanine-to-adenine transition at nucleotide position 254, which resulted in a serine-to-asparagine substitution of the bovine proteoglycan core protein. This substitution occurred in the serine-glycine dipeptide repeat that was suspected to be the binding portion of dermatan sulfate. This point mutation in the genome was also detected by the use of restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) methods. The results of the RFLP and PCR indicated that the calf was a heterozygote of an abnormal gene and a normal gene of the core protein. The interpretation of these data revealed that the functional abnormality in cutaneous tissues of the calf was caused by an abnormal gene of the proteoglycan core protein, which induced a substitution of amino acid.Journal of Veterinary Internal Medicine 13(3):202-5. · 2.22 Impact Factor
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ABSTRACT: Fragmented medial coronoid process (FCP) is the main component of elbow dysplasia (ED) in dogs, which also includes osteochondrosis of the humeral condyle (OCD), elbow incongruity (INC), and ununited anconeal process (UAP). FCP is recognized as a hereditary disease in many breeds and is a major concern in working dog breeds such as the Labrador Retriever. Different aspects of FCP were described in this thesis, such as the development of the elbow joint, possible pathogeneses of FCP, and different types of genetic investigations that could be carried out to identify the gene causing FCP. Because mal-development of bone and cartilage could cause FCP, we speculated that collagen genes could play an important role in the pathogenesis of FCP. Microsatellite markers were developed that were closely situated to different genes encoding various collagen proteins including COL1A1 (for collagen type I, subunit alpha-1), COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL6A3, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, COL11A2, and COL24A1. We found that none DNA marker alleles was shared significantly more than expected by FCP-affected sibling pairs. We concluded that the collagen genes investigated were unlikely to play an important role in the pathogenesis of FCP. We also found that COL9A1, COL9A2 and COL9A3 were unlikely to be involved in the pathogenesis of cruciate ligament rupture in Boxers. In addition, research was performed to identify FCP-genes using genome-wide, model-free linkage analysis with 320 microsatellite markers and 1536 SNP markers in parallel. These markers were evenly spread along the genome. Results identified potential FCP loci on CFA01 and CFA13, but the gene for FCP was not elucidated. Research of candidate genes at these loci is currently in progress. We investigated chondrodysplasia in Labrador Retrievers and evaluated the involvement of the genes encoding cartilage oligomeric matrix protein (COMP), COL9A1, COL9A2, and COL9A3, Matrilin-3, and solute carrier family 26 member 2 (SLC26A2) in affected dogs and their relatives. Although we did not find yet the gene responsible for chondrodysplasia in these Labrador Retrievers, we created a solid base for further investigation. We also documented hereditary radial subluxation in Bouvier des Flandres for the first time. This abnormality manifests as disproportionately short front legs with valgus deformity and disturbed configuration of the elbow. We hypothesized that the radial head subluxation in these Bouviers was the consequence of angulation of the radial bone, possibly aggravated by forces resulting from the supinatus muscle and laxity of the annular ligament. The concomitantly occurring cranial bending of the olecranon could be caused by force originating from the triceps brachii muscle. Angulation of the radius occurs at birth or soon thereafter and was seen at the mid-diaphysis of the radius, at the insertion of interosseous ligament. Genealogical analysis indicated that most affected Bouviers, originating from the Netherlands and Sweden, were closely related, but the mode of inheritance is not clear. Heredity based on genomic instability is a possible but yet unproven explanation. The molecular genetic studies as described in this thesis to identify the gene involved in FCP, could serve as a model for the investigation of other diseases of importance in companion animal orthopedics, such as chondrodysplasia and radial head subluxation.
Article: Heritable diseases of collagen.New England Journal of Medicine 09/1984; 311(6):376-86. DOI:10.1056/NEJM198408093110606 · 54.42 Impact Factor