Sarrión Patricia, Mellibovsky Leonardo, Urreizti Roser, Civit Sergi, Cols Neus, García-Giralt Natàlia, Yoskovitz Guy, Aranguren Alvaro, Malouf Jorge, Di Gregorio Silvana, Río Luís Del, Güerri Roberto, Nogués Xavier, Díez-Pérez Adolfo, Grinberg Daniel, Balcells Susana
Departament de Genètica, Universitat de Barcelona, IBUB, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain; Institut de Biomedicina Universitat de Barcelona (IBUB), Barcelona, Spain.
Unitat de Recerca en Fisiologia Òssia i Articular (URFOA), Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona, Spain; Red Tematica de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Barcelona, Spain.
PLoS One. 2014 Apr 15;9(4):e94607. doi: 10.1371/journal.pone.0094607. eCollection 2014.
The aims of the study were to establish the prevalence of high bone mass (HBM) in a cohort of Spanish postmenopausal women (BARCOS) and to assess the contribution of LRP5 and DKK1 mutations and of common bone mineral density (BMD) variants to a HBM phenotype. Furthermore, we describe the expression of several osteoblast-specific and Wnt-pathway genes in primary osteoblasts from two HBM cases. A 0.6% of individuals (10/1600) displayed Z-scores in the HBM range (sum Z-score >4). While no mutation in the relevant exons of LRP5 was detected, a rare missense change in DKK1 was found (p.Y74F), which cosegregated with the phenotype in a small pedigree. Fifty-five BMD SNPs from Estrada et al. [NatGenet 44:491-501,2012] were genotyped in the HBM cases to obtain risk scores for each individual. In this small group of samples, Z-scores were found inversely related to risk scores, suggestive of a polygenic etiology. There was a single exception, which may be explained by a rare penetrant genetic variant, counterbalancing the additive effect of the risk alleles. The expression analysis in primary osteoblasts from two HBM cases and five controls suggested that IL6R, DLX3, TWIST1 and PPARG are negatively related to Z-score. One HBM case presented with high levels of RUNX2, while the other displayed very low SOX6. In conclusion, we provide evidence of lack of LRP5 mutations and of a putative HBM-causing mutation in DKK1. Additionally, we present SNP genotyping and expression results that suggest additive effects of several genes for HBM.
本研究的目的是确定一组西班牙绝经后女性（BARCOS）中高骨量（HBM）的患病率，并评估LRP5和DKK1突变以及常见骨矿物质密度（BMD）变异对HBM表型的影响。此外，我们描述了来自两例HBM病例的原代成骨细胞中几种成骨细胞特异性基因和Wnt信号通路基因的表达情况。0.6%的个体（10/1600）的Z值处于HBM范围内（Z值总和>4）。虽然在LRP5的相关外显子中未检测到突变，但在DKK1中发现了一种罕见的错义变化（p.Y74F），该变化在一个小家系中与表型共分离。对来自Estrada等人[《自然遗传学》44:491 - 501,2012]的55个BMD单核苷酸多态性（SNP）在HBM病例中进行基因分型，以获得每个个体的风险评分。在这一小群样本中，发现Z值与风险评分呈负相关，提示存在多基因病因。有一个例外情况，这可能由一种罕见的显性遗传变异解释，抵消了风险等位基因的累加效应。对两例HBM病例和五例对照的原代成骨细胞进行的表达分析表明，IL6R、DLX3、TWIST1和PPARG与Z值呈负相关。一例HBM病例RUNX2水平较高，而另一例SOX6水平极低。总之，我们提供了LRP5无突变以及DKK1中可能存在导致HBM突变的证据。此外，我们展示了SNP基因分型和表达结果，提示多个基因对HBM有累加效应。
