Melatonin receptor 1A variants as genetic cause of idiopathic osteoporosis.

Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A () with a potential pathogenic outcome. A rare variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [c.184+1G>T ()] on bone physiology. A mouse model of the human rs374152717 variant reproduced the low bone mass (BM) phenotype of young-adult patients with IOP. Low BM occurred because of induction of senescence in mutant osteoblasts followed by compromised differentiation and function. In human cells, introduction of rs374152717 led to translation of a nonfunctional protein and subsequent dysregulation of melatonin signaling. These studies provide evidence that mutations entail a genetic etiology of IOP and establish the rs374152717 variant as a loss-of-function allele that impairs bone turnover by inducing senescence in osteoblasts. The higher prevalence of the variants identified in IOP cohorts versus the general population indicates a greater risk of IOP in those carrying these variants, especially Ashkenazi Jewish individuals bearing the rs374152717 variant.