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 ( MTNR1A ) with a potential pathogenic outcome. A rare MTNR1A variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an MTNR1A 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 [ MTNR1A c.184+1G>T ( MTNR1A 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 MTNR1A 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 MTNR1A 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.

中文翻译：

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褪黑激素受体 1A 变异是特发性骨质疏松症的遗传原因


特发性骨质疏松症 （IOP） 是一种罕见的早发性骨质疏松症，在骨流失的代谢或激素原因不明且发病机制不明的患者中被诊断出来。IOP 患者通常报告儿童骨折和骨质疏松症家族史，这增加了 IOP 遗传病因的可能性。不同 IOP 队列的全外显子组测序分析确定了褪黑激素受体 1A （ MTNR1A ） 中的多个变体，具有潜在的致病结果。在患有 IOP 的德系犹太家庭的成员中发现了罕见的 MTNR1A 变异 （rs374152717），在非亲缘关系的女性 IOP 队列中发现了 MTNR1A 变异 （rs28383653） （4%）。这两种变体在德系犹太人中的发生频率都比在普通人群中高得多。我们研究了杂合子 （rs374152717） 变体 [ MTNR1A c.184+1G>T （ MTNR1A c. 184+1G>T ）] 对骨生理学的影响。人类 rs374152717 变体的小鼠模型再现了年轻成年 IOP 患者的低骨量 （BM） 表型。低 BM 的发生是由于突变成骨细胞衰老的诱导，随后分化和功能受损。在人类细胞中，rs374152717 的引入导致非功能性蛋白质的翻译和随后的褪黑激素信号失调。这些研究提供了证据，证明 MTNR1A 突变会导致 IOP 的遗传病因，并将 rs374152717 变体确定为功能丧失等位基因，通过诱导成骨细胞衰老来损害骨更新。与一般人群相比，在 IOP 队列中发现的 MTNR1A 变异的患病率更高，这表明携带这些变异的人患 IOP 的风险更大，尤其是携带 rs374152717 变异的德系犹太人。