Abstract
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.
Highlights
In order to explore the genetic constitution of a high bone mass phenotype, our aims were, first, to establish the prevalence of HBM in the BARCOS (BARCelona OSteoporosis) cohort of postmenopausal Spanish women; second, to determine whether any of the HMB cases carried LRP5 or DKK1 mutations that could explain the phenotype; and third, to assess whether the HBM cases were carriers of a low number of risk alleles of 55 autosomal genome-wide association (GWA)-identified Bone mineral density (BMD) loci
In this study we established that the prevalence of HBM in a Spanish cohort of postmenopausal women is 0.63%
The results of the analysis of 55 osteoporosis-predisposing SNPs pointed to an inverse correlation between risk alleles and BMD in this group of HBM women, with the exception of one case with the highest BMD value and the highest risk score
Summary
BMD is distributed as a Gaussian curve in the general population, with two small groups having extremely low or extremely high BMD values at both ends These individuals with extreme phenotypes may bear infrequent and highly penetrant alleles at a few specific loci. A few individuals with high bone mass (HBM, MIM#601884), as defined by a sum Z-score .4 (total lumbar spine Z-score + total femoral neck Z-score), have been reported to bear highly penetrant missense alleles at the low-density lipoprotein receptor-related protein 5 (LRP5, MIM#603506) locus that are transmitted in an autosomal dominant way. While inactivating mutations in LRP5 were shown to cause osteoporosis-pseudoglioma syndrome [7], gain-of-function mutations caused a high bone mass (HBM) phenotype [8]. Significant phenotypic heterogeneity was reported, and some affected family members had a torus palatinus
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