Genetic variants in melatonin receptor linked to idiopathic osteoporosis

Columbia University Medical Center researchers have identified specific variants in a melatonin receptor gene that impair bone turnover, leading to significant reductions in bone density and increased risk of fractures, particularly in Ashkenazi Jewish individuals.

Osteoporosis is a common bone disorder characterized by low bone mass and increased fracture risk, usually affecting postmenopausal women and men over the age of 60.

Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis that is seen in individuals under 50 years of age without any known metabolic or hormonal causes. Family histories of osteoporosis and childhood fractures suggest a genetic basis for IOP, though many cases remain unexplained despite previous genetic studies.

In the study, “Melatonin receptor 1A variants as genetic cause of idiopathic osteoporosis,” published in Science Translational Medicine, researchers examined melatonin receptor variants as a potential genetic cause of IOP. They focused on the variant rs374152717, found in an Ashkenazi family with IOP, and rs28383653, identified in unrelated IOP patients.

Whole-exome sequencing was conducted on an Ashkenazi family affected by IOP, as well as a cohort of 75 unrelated women with IOP. The rs374152717 variant was present in individuals with IOP in the Ashkenazi family but absent in unaffected relatives.

This mutation was more frequent in the Ashkenazi population (0.9%) than in the general population (0.0004%). In the unrelated cohort, the rs28383653 variant was found in 4% of IOP patients.

A mouse model was used to investigate the functional consequences of the rs374152717 mutation. Mice carrying the human mutation exhibited low bone mass, a hallmark of osteoporosis, which the scientists traced to defects in osteoblast function.

Osteoblasts are the cells responsible for bone formation. These cells were found to experience senescence, an accelerated aging or premature shutting down of cellular activity due to the mutation. This senescent state impaired their ability to differentiate and build bone properly.

Further analysis in human cells confirmed that the rs374152717 mutation disrupted melatonin signaling, leading to the production of a dysfunctional MTNR1A protein and subsequent bone degeneration.

Melatonin signaling normally promotes bone formation and inhibits bone resorption, but the mutations caused abnormal regulation of cyclic AMP, calcium signaling, and mitogen-activated protein kinase pathways, which triggered osteoblast senescence and bone loss.

The findings point to a possible source for the mysterious idiopathic osteoporosis condition and suggest that genetic screening for MTNR1A variants could be a primary investigation for individuals with unexplained bone loss.

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