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Indiana University-Purdue University Indianapolis (IUPUI) / The characteristics of cleidocranial dysplasia were first reported in 1897 by Pierre Marie and Paul Sainton. Since this first classification of the disease, many radiographic and clinical signs have been associated with this entity. Individuals with this disease have been repeatedly described as having a relative prognathism of the mandible due to a small, retropositioned maxilla and an enlarged cranial base. The present study was designed to determine, through the use of cephalometric measurements, if there is truly a difference in the size and position of the maxilla and an enlargement of the cranial base in these affected individuals. Ten cleidocranial dysplasia patients ranging in age from three years to 53 years, and their immediate families were studied. Non-affected members were studied to provide an intrafamilial comparison of skeletal development. The data obtained from the cephalometric measurements showed that the cranial bases for this group were within normal limits, or tending towards the small size. The maxilla was of normal size and the position was normal or anteriorly positioned in all cases. The mandible was considerably larger in 70% of the affecteds studied. Radiographic investigation showed this group to have delayed ossification of cranial sutures and mandibular symphysis. Absent frontal and mastoid sinuses, orbital hypertelorism, osteopetrotic appearance of the cranium, and absent or hypoplastic nasal bones were also observed.

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No description available.

The morphologic variability seen in the domestic dog, Canis lupus familiaris, is unique among mammals. Selective pressures imposed by humans have divided dogs into almost 400 separate breeds. Selection has also led to the development of approximately 450 hereditary diseases, many of which are limited to specific breeds. Over half of these diseases present with similar clinical characteristics to those of many human hereditary diseases, making the dog an ideal model for study of the genetic bases of such diseases. Many diseases do not have candidate genes or have too many candidates to characterize. This is exacerbated in complex diseases that are caused by several genes. Whole-genome scans can provide insight into diseases by identifying marker(s) that co-segregate with a disease phenotype. The Minimal Screening Set - 2 (MSS-2) is the most recent set of microsatellites suitable for whole-genome screens. The first objective of this work was to streamline genomic screens in order to efficiently analyze large numbers of animals. To this end, chromosome-specific microsatellite panels were developed for the MSS-2. Canine hip dysplasia (CHD) is the most common orthopedic disease of the dog. CHD primarily affects medium and large breed dogs, but is found in almost every breed. The major objective of this work was to use linkage analysis to identify chromosomal regions that contain genes that are involved in CHD. Two populations were screened using the MSS-2. The first was a small family of Boykin Spaniels, though no markers were statistically significant in a whole-genome screen. An outcrossed pedigree of Greyhound/Labrador Retrievers was created for quantitative trait loci (QTL) mapping of CHD. The informativeness of markers in the F2 and backcrossed generations were calculated to show the utility of using such a population. Other factors that affect the power of this pedigree to identify QTL were also highlighted. Chromosomes that were identified in a previous screen as harboring putative QTLs were examined using the chromosome-specific panels to further define and confirm the regions of interest. Although no markers reached statistical significance, several areas of interest were identified.

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Abstract The nucleotide sequence of the entire COL9A3 gene, coding for the human α3(IX) chain, was determined. The gene was approximately 23 kb in length and consisted of 32 exons. The polymerase chain reaction (PCR)-based procedure of conformation-sensitive gel electrophoresis (CSGE) was used to screen the gene for sequence variations and mutations in 83 unrelated patients with generalized primary osteoarthritis (OA), 31 with rheumatoid arthritis (RA), 171 with intervertebral disc disease (IDD), and 50 with various osteochondrodysplasias. The frequencies of certain sequence variations in healthy individuals were also determined. The COL9A3 gene was analyzed for mutations in two unrelated families with multiple epiphyseal dysplasia (MED). The analysis revealed a splice site mutation leading to skipping of exon 3 and an in-frame loss of 12 amino acid residues in the COL3 domain, the first diseasecausing mutation to be identified in the COL9A3 gene. Sequencing also indicated a 9 bp deletion in one allele in the second MED family that removed a Gly-Pro-Pro triplet. Surprisingly, the deletion did not co-segregate with the MED phenotype in the family. A similar 9 bp deletion, was also found in an unrelated family with no obvious phenotype, suggesting that the two 9 bp deletions represent neutral sequence variants. A construct with the deletion was then made in order to produce a recombinant protein, and the mutant type IX collagen was analyzed under reducing conditions by SDS-PAGE. The results indicated that the recombinant type IX collagen proteins consisted of three α chains, α1(IX), α2(JX), α3(IX), in a 1:1:1 ratio. To study the triple helix stability, pepsin treatment followed by SDS-PAGE was performed on normally folded and denatured recombinant type IX collagen samples. The results demonstrated that the recombinant type IX collagen containing the Gly-X-Y deletion in the a3(IX) chain is secreted as a correctly folded triple-helical molecule. CSGE analysis of exon 5 of the COL9A3 gene identified two nucleotide variations in the same codon, and thus three alleles: CGG (Arg), CAG (Gln), and TGG (Trp). The frequency of the Trp for Arg substitution, the Trp3 allele, was 0.244 among the probands with the IDD, while its overall frequency in the combined group of all non-IDD cases was 0.093. This difference was significant, with a p-value of 0.000013. The Trp3 allele increases the relative risk of IDD by a factor of 2.6 (95 percent confidence interval, 1.6 to 4.3). COL9A3 mutations are shown to be associated with mild cartilage and intervertebral disc diseases.

Abstract The role of sequence variations in genes encoding cartilage extracellular matrix (ECM) proteins were studied in osteoarthritis (OA) and multiple epiphyseal dysplasia (MED). The cartilage collagen genes COL2A1, COL9A1, COL9A2, COL9A3, COL11A1, and COL11A2 were screened for sequence variations in 72 Finnish probands and one US family with primary early-onset hip and/or knee OA. Altogether 239 sequence variations were found, of which 16 were not present in the controls. Seven of the unique variations — four in COL11A1, two in COL11A2, and one in COL2A1 — were studied further, because they resulted in the substitution of conserved amino acids or were predicted to affect mRNA splicing. Association analysis was performed by genotyping 6–12 common polymorphisms from each gene in 72 OA patients and 103 controls; no common predisposing alleles were identified. The results, however, suggest that mutations in the minor cartilage collagen genes can be the cause of OA in a subgroup of OA patients. Two MED families with clinical and radiographic features suggestive of a collagen IX mutation were studied. Mutation screening of COL9A1, COL9A2, and COL9A3 yielded negative results. Instead, an R718W mutation in COMP was identified in both families. Clinical and radiographic overlap between patients with collagen IX mutations and patients with COMP mutations points to a common supramolecular complex pathogenesis. Clinical, radiological and molecular analyses of known MED genes were performed on a cohort of 29 consecutive MED patients. The DTDST mutation was identified in four patients (14%), the COMP mutation in three (10%), and the MATN3 mutation in three (10%). Two new distinct phenotypic entities were identified in patients in whom no mutation was found. The findings suggest that mutations in the above mentioned known MED genes are not the major cause of MED and are responsible for less than half of the cases. The existence of additional MED loci is supported by the exclusion of known loci and finding of the specific subgroups among these patients. The results suggest that genetic defects in ECM genes can predispose to OA and cause MED, even though the major genes involved in both disorders remain to be found.

No description available.

Twelve normal mixed-breed dogs were selected and assigned to acetabular rotation or sham-operated groups. Rotation group dogs had pelvic osteotomies followed by application of an ilial bone plate, causing rotation of the acetabulum to reduce dorsal coverage of the femoral head. Sham group dogs received identical osteotomies but were plated in normal orientation. All dogs had force plate and subjective lameness evaluations pre-operatively and post-operatively. Pelvic radiographs were evaluated pre-operatively and at four-week intervals post-operatively. The dogs were killed at the conclusion of the study, and samples were taken for evaluation. Analysis of vertical ground reaction forces indicated a significant difference between treatment groups, however no difference was noted based on subjective scores. No difference was observed between groups based on radiographic estimations of degenerative changes or Norberg angle, however the coverage of the femoral head was less in rotated dogs. Mild inflammatory changes were discernible in the joint capsule of some dogs in both groups. A trend toward more severe change was present in the left hip of the treatment group, but statistically significant difference was noted only when comparing the right and left legs of the acetabular rotation group. Although evidence of osteoarthritis was noted histologically, only minor differences were detected in the dogs by other means. Because of the minimal changes noted over the duration of the study, we conclude that the model does result in histopathologic change consistent with osteoarthritis, but that force plate analysis, radiographic evaluation, and clinical lameness evaluation are insensitive measures of this change. / Master of Science