Linkage of a Gene Causing High Bone Mass to Human Chromosome 11 (11q12-13)

Johnson, Mark; Gong, Gordon; Kimberling, William J.; Recker, Susan M.; Kimmel, Donald B.; Recker, Robert R.

doi:10.1086/515470

Cited by 293 publications

(208 citation statements)

References 30 publications

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“…Two groups have previously reported lod scores suggestive of linkage of bone density to chromosome 11q 20,21 with a maximum at the locus D11S987. This marker is located near the centromere, probably within 11q12.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 Linkage and association studies have suggested that some other genes that condition BMD are the vitamin D receptor (see 18 for review) and the estrogen receptor. 19 Linkage studies in two disorders, osteoporosis-pseudoglioma syndrome 20 and a high bone mass trait 21 indicate that a gene or genes on chromosome 11q can influence bone density.…”

Section: Introductionmentioning

confidence: 99%

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First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q

Devoto

Shimoya

Caminis³

et al. 1998

Eur J Hum Genet

208

139

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Osteoporosis is characterized by low bone density, and osteopenia is responsible for 1.5 million fractures in the United States annually. 1 In order to identify regions of the genome which are likely to contain genes predisposing to osteopenia, we genotyped 149 members of seven large pedigrees having recurrence of low bone mineral density (BMD) with 330 DNA markers spread throughout the autosomal genome. Linkage analysis for this quantitative trait was carried out using spine and hip BMD values by the classical lod-score method using a genetic model with parameters estimated from the seven families. In addition, non-parametric analysis was performed using the traditional Haseman-Elston approach in 74 independent sib pairs from the same pedigrees. The maximum lod score obtained by parametric analysis in all families combined was + 2.08 (θ = 0.05) for the marker CD3D on chromosome 11q. All other combined lod scores from the parametric analysis were less than + 1.90, the threshold for suggestive linkage. Non-parametric analysis suggested linkage of low BMD to chromosomes 1p36 (Z max = + 3.51 for D1S450) and 2p23-24 (Z max = + 2.07 for D2S149). Maximum multi-point lod scores for these regions were + 2.29 and + 2.25, respectively. A third region with associated lod scores above the threshold of suggestive linkage in both singlepoint and multi-point non-parametric analysis was on chromosome 4qter (Z max = + 2.95 for D4S1539 and Z max = + 2.48 for D4S1554). Our data suggest the existence of multiple genes involved in controlling spine and hip BMD, and indicate several candidate regions for further screening in this and other independent samples.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q

Devoto

Shimoya

Caminis³

et al. 1998

Eur J Hum Genet

208

139

View full text Add to dashboard Cite

show abstract

“…The embryonic expression pattern of Wnt11, particularly its restricted expression to the perichondrium of the developing skeleton, has long suggested its role in skeletal development 138. Interestingly, the chromosomal location of Wnt11 to 11q13.5 is near previously linked markers of high bone mass 138, 139. In addition, Wnt11 expression is upregulated during mesenchymal osteogenesis 140.…”

Section: Implication Of Noncanonical Wnt Signaling In Vcmentioning

confidence: 99%

Atherosclerotic Calcification: Wnt Is the Hint

Albanese

Khan

Barratt

et al. 2018

JAHA

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“…The LRP5 pathway was discovered to be a key regulator of bone mass following linkage studies in two rare human diseases: OPPS, which is a recessively inherited condition characterized by severe, early onset osteoporosis and congenital blindness due to vitreous opacity (Gong et al 1998), and the HBM syndrome that is an asymptomatic autosomal dominant disorder characterized by increased bone mineral density (Johnson et al 1997). Both of these conditions were mapped to the same region of chromosome 11q12 in the late 1990s, and different mutations in the LRP5 gene were eventually identified as the cause of both disorders by positional cloning studies (Gong et al 2001;Little et al 2002).…”

Section: Lipoprotein Receptor-related Protein 5 (Lrp5)mentioning

confidence: 99%

Genetic regulation of bone mass and susceptibility to osteoporosis

Ralston¹,

Crombrugghe²

2006

Genes Dev.

291

229

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Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that the heritability of bone mineral density (BMD) and other determinants of fracture risksuch as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.Osteoporosis is characterized by reduced bone mass, alterations in the microarchitecture of bone tissue, reduced bone strength, and an increased risk of fracture (Kanis et al. 1994). Osteoporosis is a common condition that affects up to 30% of women and 12% of men at some point in life. The prevalence of osteoporosis increases with age due to an imbalance in the rate at which bone is removed and replaced during the bone remodeling cycle, which is an important physiological process that is essential for maintenance of a healthy skeleton. Many factors influence the risk of osteoporosis-including diet, physical activity, medication use, and coexisting diseases-but one of the most important clinical risk factors is a positive family history, emphasizing the importance of genetics in the pathogenesis of osteoporosis. In this article, we first review the evidence for a genetic contribution to osteoporosis and related phenotypes, and discuss the mechanisms by which mutations and polymorphisms in genes that regulate susceptibility to osteoporosis affect major signaling pathways in bone. Genetic influences on osteoporosisGenetic factors have long been recognized as playing an important role in the pathogenesis of osteoporosis. Evidence from twin and family studies suggests that between 50% and 85% of the variance in peak bone mass is genetically determined, depending on skeletal site and the age of the subjects studied (Smith et al. 1973;Pocock et al. 1987;Krall and Dawson-Hughes 1993;Gueguen et al. 1995). Heritability studies have also shown evidence of significant genetic effects on other key determinants of osteoporotic fracture risk, including quantitative ultrasound properties of bone (Arden et al. 1996), femoral neck geometry (Arden et al. 1996), muscle strength (Arden and Spector 1997), bone turnover markers (Hunter et al. 2001), and body mass index (Kaprio et al. 1995). The role of genetic factors in the pathogenesis of bon...

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Linkage of a Gene Causing High Bone Mass to Human Chromosome 11 (11q12-13)

Cited by 293 publications

References 30 publications

First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q

First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q

Atherosclerotic Calcification: Wnt Is the Hint

Genetic regulation of bone mass and susceptibility to osteoporosis

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