Identification of Rare LRP5 Variants in a Cohort of Males with Impaired Bone Mass.

Maria Santa Rocca,Maria Bueno Marinas,Carlo Foresta,Alberto Ferlin,Giovanni Minervini,Andrea Garolla,Luca De Toni,Andrea Di Nisio,Kalliopi Pilichou,Maurizio Merico

doi:10.3390/ijms221910834

Abstract

Osteoporosis is the most common bone disease characterized by reduced bone mass and increased bone fragility. Genetic contribution is one of the main causes of primary osteoporosis; therefore, both genders are affected by this skeletal disorder. Nonetheless, osteoporosis in men has received little attention, thus being underestimated and undertreated. The aim of this study was to identify novel genetic variants in a cohort of 128 males with idiopathic low bone mass using a next-generation sequencing (NGS) panel including genes whose mutations could result in reduced bone mineral density (BMD). Genetic analysis detected in eleven patients ten rare heterozygous variants within the LRP5 gene, which were categorized as VUS (variant of uncertain significance), likely pathogenic and benign variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. Protein structural and Bayesian analysis performed on identified LRP5 variants pointed out p.R1036Q and p.R1135C as pathogenic, therefore suggesting the likely association of these two variants with the low bone mass phenotype. In conclusion, this study expands our understanding on the importance of a functional LRP5 protein in bone formation and highlights the necessity to sequence this gene in subjects with idiopathic low BMD.

Highlights

Osteoporosis is the most common skeletal disorder characterized by reduced bone mineral density (BMD), resulting in an increased risk of fragility fractures [1]
Of the detected nonsynonymous variants, 10 heterozygous missense variants had a minor allele frequency (MAF) lower than 1% and were localized within the Lipoprotein-Related Receptors 5 (LRP5) gene
Osteoporosis is a polygenic disorder that affects about one in three women and one in five men over the age of 50 years [27]. It has been extensively studied in postmenopausal women, it is likely that this skeletal disorder may be underestimated and undertreated in male subjects, due to the low number of male subjects undergoing bone density scanning [8]

Summary

Introduction

Osteoporosis is the most common skeletal disorder characterized by reduced bone mineral density (BMD), resulting in an increased risk of fragility fractures [1]. Genome-Wide Association Studies (GWASs) have, identified genetic variants associated with an increased risk of fractures in genes encoding proteins that are involved in the metabolic balance of osteoblasts/osteoclasts [6,7]. Osteoporosis affects both genders, it has been mostly studied in postmenopausal women due to hormonal imbalances as compared to men. This could explain why, for a long time, osteoporosis has been underestimated and undertreated in male patients [8]

Objectives

Methods

Results

Conclusion