Activating mutations in the genes for fibroblast growth factor receptors 1-3 (FGFR1-3) are responsible for a diverse group of skeletal disorders. In general, mutations in FGFR1 and FGFR2 cause the majority of syndromes involving craniosynostosis, whereas the dwarfing syndromes are largely associated with FGFR3 mutations. Osteoglophonic dysplasia (OD) is a "crossover" disorder that has skeletal phenotypes associated with FGFR1, FGFR2, and FGFR3 mutations. Indeed, patients with OD present with craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as the rhizomelic dwarfism and nonossifying bone lesions that are characteristic of the disorder. We demonstrate here that OD is caused by missense mutations in highly conserved residues comprising the ligand-binding and transmembrane domains of FGFR1, thus defining novel roles for this receptor as a negative regulator of long-bone growth.

ADO2 is an uncommon sclerosing bone disorder with incomplete penetrance and variable expressivity. Positional candidate studies were performed to identify the gene responsible for ADO2. In 11 of 12 kindreds, five different missense mutations were identified in the ClCN7 gene, indicating the genetic basis and possible dominant negative mechanism for ADO2.Introduction: Autosomal dominant osteopetrosis, type II (ADO2) is an uncommon sclerosing bone disorder with a distinct radiographic appearance and unique clinical characteristics. We present the results from our genetic studies designed to identify the ADO2 gene through a positional candidate approach. Methods: Having identified 12 families with ADO2, we initially performed linkage studies in our seven largest kindreds and observed a summed maximum LOD score of 15.91 at marker D16S521 on chromosome 16p13.3. Critical meiotic recombination events further narrowed the putative gene region to a 7.6-cM area, which contains the candidate genes ATP6L and chloride channel 7 (ClCN7). We screened affected individuals from each ADO2 family for mutations in these genes using direct sequencing. Identified mutations were subsequently confirmed through direct sequencing or restriction fragment length polymorphism analysis. We then calculated the overall disease penetrance rate after all available at-risk family members were assessed for ClCN7 gene mutations. Results:No ATP6L mutations were identified in affected subjects. Subsequently, as ClCN7 gene mutations were being reported, we identified two novel (L213F, R762L) and three known (G215R, R286W, R767W) missense mutations in 11 kindreds. In our large sample, disease penetrance was 66% (62 clinically affected individuals/94 subjects with the gene mutation). To date, nine different mutations have been discovered in the ClCN7 gene in 22 of 23 ADO2 families studied. Conclusions:We conclude that mutations in the ClCN7 gene are responsible for ADO2 and that genetic heterogeneity is unlikely to exist in this disorder. Based on the preponderance of missense mutations and the knowledge that chloride channels probably function as dimers, it seems that heterozygous ClCN7 gene mutations may cause ADO2 through a dominant negative mechanism.

This study demonstrates that BMD in healthy men is highly heritable with similar estimates of the genetic contribution to BMD in both whites and blacks. Of the six QTL identified, three were specific for spine BMD and three were specific for hip BMD. When compared with published QTL for peak BMD in women from the same geographical region, four of the QTL appeared to be male specific. The occurrence of sex-specific genes in humans for BMD has potentially important implications for the pathogenesis and treatment of osteoporosis.

Peak bone mineral density (BMD) is a highly heritable trait and is a good predictor of the risk of osteoporosis and fracture in later life. Recent studies have sought to identify the genes underlying peak BMD. Linkage analysis in a sample of 464 premenopausal white sister pairs detected linkage of spine BMD to chromosome 1q (LOD 3.6). An independent sample of 254 white sister pairs has now been genotyped, and it also provides evidence of linkage to chromosome 1q (LOD 2.5) for spine BMD. Microsatellite markers were subsequently genotyped for a 4-cM map in the chromosome 1q region in all available white sister pairs (n=938), and a LOD score of 4.3 was obtained near the marker D1S445. Studies in the mouse have also detected evidence of linkage to BMD phenotypes in the region syntenic to our linkage finding on chromosome 1q. Thus, we have replicated a locus on 1q contributing to BMD at the spine and have found further support for the region in analyses employing an enlarged sample. Studies are now ongoing to identify the gene(s) contributing to peak spine BMD in women.

In humans, peak bone mineral density (BMD) is the primary determinant of osteoporotic fracture risk among older individuals, with high peak BMD levels providing protection against osteoporosis in the almost certain event of bone loss later in life. A genome screen to identify quantitative trait loci (QTLs) contributing to areal BMD (aBMD) and volumetric BMD (vBMD) measurements at the lumbar spine and femoral neck was completed in 595 female F2 rats produced from reciprocal crosses of inbred Fischer 344 and Lewis rats. Significant evidence of linkage was detected to rat Chromosomes 1, 2, 8, and 10, with LOD scores above 8.0. The region on rat Chromosome 8 is syntenic to human Chromosome 15, where linkage to spine and femur BMD has been previously reported and confirmed in a sample of premenopausal women.

A genome-wide genetic linkage analysis identified several chromosomal regions influencing bone strength and structure in F2 progeny of Fischer 344 × Lewis inbred rats.Introduction: Inbred Fischer 344 (F344) and Lewis (LEW) rats are similar in body size, but the F344 rats have significantly lower BMD and biomechanical strength of the femur and spine compared with LEW rats. The goal of this study was to identify quantitative trait loci (QTL) linked to bone strength and structure in adult female F2 rats from F344 and LEW progenitors. Materials and Methods:The 595 F2 progeny from F344 × LEW rats were phenotyped for measures of bone strength (ultimate force [Fu]; energy to break [U]; stiffness [S]) of the femur and lumbar vertebra and structure (femur midshaft polar moment of inertia [Ip]; femur midshaft cortical area; vertebral area). A genome-wide scan was completed in the F2 rats using 118 microsatellite markers at an average interval of 20 cM. Multipoint quantitative linkage analysis was performed to identify chromosomal regions that harbor QTL for bone strength and structure phenotypes. Results: Evidence of linkage for femur and lumbar strength was observed on chromosomes (Chrs) 1, 2, 5, 10, and 19. Significant linkage for femoral structure was detected on Chrs 2, 4, 5, 7, and 15. QTLs affecting femoral strength on Chrs 2 and 5 were also found to influence femur structure. Unique QTLs on Chrs 1, 10, and 19 were found that contributed to variability in bone strength but had no significant effect on structure. Also, unique QTLs were observed on Chrs 4, 7, and 15 that affected only bone structure without any effect on biomechanics. Conclusion:We showed multiple genetic loci influencing bone strength and structure in F344 × LEW F2 rats. Some of these loci are homologous to mouse and human chromosomes previously linked to related bone phenotypes.

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