Scientists from the National University Hospital of Iceland and the University of Iceland together with researchers at deCODE genetics and Illumina, reported today in the journal Nature[1] that they have identified a rare nonsense mutation called leucine-rich-repeat-containing G-protein-coupled receptor 4 (LRG4) that confers high risk of osteoporosis and osteoporosis related traits. The mutation was also found to dramatically increase the risk of numerous cancers, including squamous cell carcinoma of the skin, biliary tract cancer, and promote an imbalance in blood electrolytes and late onset of menarche

LGR4 is part of a subfamily of orphan G protein-coupled receptors (GPCRs) related to the glycoprotein hormone receptors [2]”Our findings strongly implicate the LRG4 in the pathogenesis of osteoporosis as well as various other human diseases, including certain cancers,” noted study lead author Kari Stef?nsson, M.D., Dr. Med., President of deCODE Genetics. “That this one mutation increases the risk of many diseases is not surprising. The mutation impacts an important signaling pathway known as Wnt, that contributes to the function of many cell types.”

In this study, the research team searched for gene mutations-or other variations in the genome-that may have a direct effect on the risk of pathologically low-bone density among a large set of sequence variants.

Using deCODE’s whole genome sequencing of 2,230 Icelanders, 34 million sequence variants were identified and subsequently analyzed against 4,931 persons with low-bone density disease and a large control population. From this approach, the research team discovered the nonsense mutation in LGR4 and its large effect on osteoporosis and osteoporosis related traits.

Low bone mineral density
Low bone mineral density (BMD) or bone mass, referring to the density of minerals (such as calcium) in human bones, is used as a parameter of osteoporosis. Genome-wide association studies of BMD generally focus BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. However, in their study, the researchers used BMD to find variants that have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population.

The researchers found that this rare nonsense mutation within the LGR4 gene (c.376C>T) leads to termination of LGR4 at position 126 and fully disrupts its function. The effect of the c.376C>T mutation on many other conditions was further investigated taking advantage of a large number of human diseases and other traits that are available at deCODE. Through this effort the mutation was also found to increase the risk of squamous cell carcinoma of the skin and biliary tract cancer as well as to cause blood electrolyte imbalance and late onset of menarche. The T mutation is also associated with reduced testosterone levels.

[1]Styrkarsdottir U, Thorleifsson G, Sulem P, Gudbjartsson DF, Sigurdsson A, Jonasdottir A, Jonasdottir A, et al. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature (2013)- Online; doi:10.1038/nature12124
[2]Hsu SY, Liang SG, Hsueh AJ (1998) Characterization of two lgr genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol Endocrinol 1998 Dec. 12 (12): 1830?1845

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