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Mice harboring the Col1a2(oim) mutation (oim) express dentinogenesis imperfecta. To determine the effect of Col1a2 genotype on tissue mechanical properties, we compared Young's modulus and hardness of dentin in the 3 Col1a2 genotypes. Upper incisors were tested by nanoindentation. Genotype had a significant effect on Young's modulus, but there was not a simple mutant allele dosage relationship. The effect of genotype on hardness did not reach significance. Hardness and Young's modulus were greater near the dento-enamel junction than near the pulp chamber. Greater hardness and Young's modulus values near the dento-enamel junction reflected continued mineralization of the dentin following its initial synthesis. Analysis showed the mechanical data to be consistent with Fourier transform infrared and backscattered electron microscopy studies that revealed increased mineralization in oim bone. Analysis of the data suggests that clinical fragility of teeth in oim mice is not due to deficiencies of hardness or Young's modulus, but may be due to defects in post-yield behavior or resistance to fatigue damage. [ABSTRACT FROM AUTHOR]

Mice harboring the Col1a2(oim) mutation (oim) express dentinogenesis imperfecta. To determine the effect of Col1a2 genotype on tissue mechanical properties, we compared Young's modulus and hardness of dentin in the 3 Col1a2 genotypes. Upper incisors were tested by nanoindentation. Genotype had a significant effect on Young's modulus, but there was not a simple mutant allele dosage relationship. The effect of genotype on hardness did not reach significance. Hardness and Young's modulus were greater near the dento-enamel junction than near the pulp chamber. Greater hardness and Young's modulus values near the dento-enamel junction reflected continued mineralization of the dentin following its initial synthesis. Analysis showed the mechanical data to be consistent with Fourier transform infrared and backscattered electron microscopy studies that revealed increased mineralization in oim bone. Analysis of the data suggests that clinical fragility of teeth in oim mice is not due to deficiencies of hardness or Young's modulus, but may be due to defects in post-yield behavior or resistance to fatigue damage.

Fracture susceptibility depends jointly on bone mineral content (BMC), gross bone anatomy, and bone microarchitecture and quality. Overall, it has been estimated that 50-70% of bone strength is determined genetically. Because of the difficulty of performing studies of the genetics of bone strength in humans, we have used the HcB/Dem series of recombinant congenic (RC) mice to investigate this phenotype. We performed a comprehensive phenotypic analysis of the HcB/Dem strains including morphological analysis of long bones, measurement of ash percentage, and biomechanical testing. Body mass, ash percentage, and moment of inertia each correlated moderately but imperfectly with biomechanical performance. Several chromosome regions, on chromosomes 1, 2, 8, 10, 11, and 12, show sufficient evidence of linkage to warrant closer examination in further crosses. These studies support the view that mineral content, diaphyseal diameter, and additional nonmineral material properties contributing to overall bone strength are controlled by distinct sets of genes. Moreover, the mapping data are consistent with the existence of pleiotropic loci for bone strength-related phenotypes. These findings show the importance of factors other than mineral content in determining skeletal performance and that these factors can be dissected genetically.

As the population ages, fragility fractures grow in importance as a public health problem. The principal goal of osteoporosis therapy is primary and secondary fracture prevention. A growing choice of therapies is now available for the treatment of osteoporosis. In this article, we review their efficacy using fracture prevention as an end point. The considerable heterogeneity among studies with regard to patient age, past fracture history, fracture site, and analytical methods precludes the possibility of performing a meaningful meta-analysis. Fracture outcomes have been reported in clinical trials with calcium supplementation, vitamin D supplementation, estrogen replacement therapy (ERT), calcitonin, etidronate, alendronate, sodium fluoride (NaF), parathyroid hormone (PTH), and raloxifene. Compelling evidence for fracture prevention has been provided for calcium and vitamin D supplementation and alendronate treatment. Evidence of fracture prevention exists for ERT, raloxifene, calcitonin, etidronate, and PTH. Data on NaF are inconsistent. Across agents, there is a trend toward greater efficacy for patients at greatest risk of fracture.

Idiopathic scoliosis (IS) is a common but poorly understood syndrome. Congenital scoliosis (CS) is less common but comparably unexplored. Previous studies suggest that each has a significant genetic component. However, the occurrence of scoliosis in the presence of other hereditary connective tissue syndromes raises the possibility that IS and CS are in fact a heterogeneous group of disorders with varied pathogenetic mechanisms. Mouse mutations have proven informative in identifying genes that are important in the development of the musculoskeletal system and provided important mechanistic insights regarding their roles in human disease. We sought to identify candidate genes for human IS and CS by reviewing mouse mutations with phenotypes affecting the axial skeleton. We performed a systematic review using the Mouse Genome Database (MGD), the Genome Database (GDB), and the Online Mendelian Inheritance in Man (OMIM) world-wide-web sites with additional searches performed based on the results of this initial search. We identified approximately 400 mouse mutations, reviewed approximately 250 of these for vertebral phenotypes, assessed 45 of these for synteny conservation between mouse and man, and identified 28 mouse mutations for which 29 credible candidates for human scoliosis could be identified based on mouse phenotypic and mapping data. For each of these, we have synthesized information about the mouse mutant phenotype, mapping data, information regarding molecular pathogenesis when a specific causative gene has been identified, and information regarding plausible candidates based on map position when the causative gene has not been identified. Among these were three loci for which the mutant gene had been identified and the human homologue was known. Some of the mouse mutants have phenotypes similar to human syndromes.

Most medical genetic studies seek to answer one of two questions: What genes are important in determining disease risk? and What alleles of a candidate gene confer excess risk? This article seeks to provide physicians with a practical approach to assessing articles on genetic topics, using examples from bone mineral density and related areas. First, this article reviews the essential features of meiosis, crossing over, and allele detection. Second, mapping strategies are described and illustrated. Third, this article considers studies of the association between alleles of specific candidate genes and bone phenotypes. Linkage without association and association without linkage are both possible. Fourth, the ability of studies using inbred mice to establish both linkage and association is explained. Fifth, the transmission disequilibrium test is proposed as a superior design for investigating the association of alleles with bone phenotypes. Sixth and last, a systematic approach to reading medical genetic studies critically is developed. Common shortcomings in published articles include insufficient evidence for candidate choice, confusion between functionally significant alleles and markers, and failure to distinguish between identity by descent and identity by state.

Background: Multiple endocrine neoplasia type 2 (MEN 2) is a group of related autosomal dominant cancer syndromes caused by mutations in the RET protooncogene. A subset of familial Hirschsprung's disease, aganglionic megacolon, is also caused by mutations in this gene., Methods: The authors performed mutation analysis of exons 10, 11, 13, and 16 of the RET gene is six established MTN 2 kindreds and in six patients with apparent sporadic disease, in order to correlate their genotypes and phenotypes., Results: One of these kindred's carried both Hirschsprung's disease and MEN 2A in conjunction with a cysteine-to-arginine substitution of codon 620 of the RET gene. One patient with apparently sporadic disease was found to have a germline M918T mutation. Patients with confirmed familial disease all carried pathologic germline mutations of RET., Conclusions: Several lines of evidence support a gain of function mechanism for tumorigenesis in the MEN 2 syndromes but a loss of function mechanism for aganglionosis in Hirschsprung's disease. The authors propose that a multihit mechanism can reconcile the apparent paradox of a single mutation that gives rise to both gain and loss of function disorders in a single patient.

The myc family of proto-oncogenes consists of at least three members, whose expression is tightly and co-ordinately regulated. The genes are nevertheless dispersed to three distinct chromosomal sites in humans. We have now used somatic cell genetics and the analysis of restriction fragment length polymorphisms (RFLPs) to identify and chromosomally map two mouse N-myc loci, to chromosomes 12 and 5, and two L-myc loci, provisionally to chromosomes 4 and 12. The second locus in each pair may be a pseudogene.