Early-Onset Osteoporosis: Molecular Analysis in Large Cohort and Focus on the PLS3 Gene.

IF 3.3 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Calcified Tissue International Pub Date : 2024-11-01 Epub Date: 2024-09-24 DOI:10.1007/s00223-024-01288-z
Maxence Mancini, Roland Chapurlat, Bertrand Isidor, Marine Desjonqueres, Guillaume Couture, Pascal Guggenbuhl, Régis Coutant, Salima El Chehadeh, Mélanie Fradin, Aline Frazier, Alice Goldenberg, Pascaline Guillot, Eugénie Koumakis, Nadia Mehsen-Cêtre, Massimiliano Rossi, Élise Schaefer, Sabine Sigaudy, Valérie Porquet-Bordes, Élisabeth Fontanges, Pauline Letard, Thomas Edouard, Rose-Marie Javier, Martine Cohen-Solal, Thomas Funck-Brentano, Corinne Collet
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引用次数: 0

Abstract

Osteoporosis is a skeletal disorder characterized by abnormal bone microarchitecture and low bone mineral density (BMD), responsible for an increased risk of fractures and skeletal fragility. It is a common pathology of the aging population. However, when osteoporosis occurs in children or young adults, it strongly suggests an underlying genetic etiology. Over the past two decades, several genes have been identified as responsible for this particular kind of considered monogenic early-onset osteoporosis (EOOP) or juvenile osteoporosis, the main ones being COL1A1, COL1A2, LRP5, LRP6, WNT1, and more recently PLS3. In this study, the objective was to characterize a large cohort of patients diagnosed with primary osteoporosis and to establish its diagnosis yield. The study included 577 patients diagnosed with primary osteoporosis and its diagnosis yield was established. To this end, next-generation sequencing (NGS) of a panel of 21 genes known to play a role in bone fragility was carried out. A genetic etiology was explained in about 18% of cases, while the others remain unexplained. The most frequently identified gene associated with EOOP is LRP5, which was responsible for 8.2% of the positive results (47 patients). As unexpected, 17 patients (2.9%) had a variant in PLS3 which encodes plastin 3. Alterations of PLS3 are associated with dominant X-linked osteoporosis, an extremely rare disease. Given the rarity of this disease, we focused on it. It was observed that males were more affected than females, but it is noteworthy that three females with a particularly severe phenotype were identified. Of these three, two had a variant in an additional gene involved in EOP, illustrating the probable existence of digenism. We significantly increase the number of variants potentially associated with EOOP, especially in PLS3. The results of our study demonstrate that molecular analysis in EOOP is beneficial and useful.

早发骨质疏松症:大型队列中的分子分析和 PLS3 基因。
骨质疏松症是一种骨骼疾病,其特点是骨微结构异常和骨矿物质密度(BMD)低,导致骨折和骨骼脆弱的风险增加。它是老龄人口的常见病。然而,当骨质疏松症发生在儿童或年轻人身上时,则强烈提示其潜在的遗传病因。在过去的二十年里,有几个基因已被确定为导致这种被认为是单基因早发型骨质疏松症(EOOP)或青少年骨质疏松症的原因,主要基因包括 COL1A1、COL1A2、LRP5、LRP6、WNT1 和最近的 PLS3。本研究的目的是描述一大批确诊为原发性骨质疏松症患者的特征,并确定其诊断率。研究纳入了 577 名确诊为原发性骨质疏松症的患者,并确定了其诊断率。为此,研究人员对已知在骨脆性中发挥作用的 21 个基因进行了新一代测序(NGS)。约 18% 的病例解释了遗传病因,而其他病例仍无法解释。与 EOOP 相关的最常见基因是 LRP5,在阳性结果中占 8.2%(47 名患者)。出乎意料的是,17 名患者(2.9%)的编码塑蛋白 3 的 PLS3 基因出现了变异。PLS3 的变异与显性 X 连锁骨质疏松症有关,这是一种极为罕见的疾病。鉴于这种疾病的罕见性,我们对其进行了重点研究。据观察,男性患者多于女性,但值得注意的是,我们发现了三名表型特别严重的女性患者。在这三个人中,有两个人的基因变异与 EOP 有关,这说明可能存在二基因遗传。我们大大增加了可能与 EOOP 相关的变体数量,尤其是 PLS3 中的变体。我们的研究结果表明,对 EOOP 进行分子分析是有益和有用的。
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来源期刊
Calcified Tissue International
Calcified Tissue International 医学-内分泌学与代谢
CiteScore
8.00
自引率
2.40%
发文量
112
审稿时长
4-8 weeks
期刊介绍: Calcified Tissue International and Musculoskeletal Research publishes original research and reviews concerning the structure and function of bone, and other musculoskeletal tissues in living organisms and clinical studies of musculoskeletal disease. It includes studies of cell biology, molecular biology, intracellular signalling, and physiology, as well as research into the hormones, cytokines and other mediators that influence the musculoskeletal system. The journal also publishes clinical studies of relevance to bone disease, mineral metabolism, muscle function, and musculoskeletal interactions.
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