An LRP6 mutation (Arg360His) associated with low bone mineral density but not cardiovascular events in a Caucasian family

Abstract

We present a family with a rare mutation of the LRP6 gene and for the first time provide evidence for its association with low bone mineral density. Introduction The Wnt pathway plays a critical role in bone homeostasis. Pathogenic variants of the Wnt co-receptor LRP6 have been associated with abnormal skeletal phenotypes or increased risk of cardiovascular events. Patient and methods Here we report an index premenopausal patient and her family carrying a rare missense LRP6 pathogenic variant (rs141212743; 0.0002 frequency among Europeans). This variant has been previously associated with metabolic syndrome and atherosclerosis, in the presence of normal bone mineral density. However, the LRP6 variant was associated with low bone mineral density in this family, without evidence for association with serum lipid levels or cardiovascular events. Conclusion Thus, this novel association shows that LRP6 pathogenic variants may be involved in some cases of early-onset osteoporosis, but the predominant effect, either skeletal or cardiovascular, may vary depending on the genetic background or other acquired factors.

TC and LDL-C are negatively correlated with bone mineral density in patients with osteoporosis

“…Intermediate metabolites activate estrogen receptors [42] and liver X receptors [43] to promote osteoclastogenesis and inhibit osteogenesis. In humans, mutations in the LDL receptor-related protein 6 (LRP6) gene are associated with severe osteoporosis concurrent with high serum LDL-C levels [44]. Therefore, high concentrations of LDL-C and TC reduce bone formation and have an adverse effect on patient BMD, inducing the occurrence of osteoporosis.…”

LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low‐Density Lipoprotein Receptor‐Related Protein 6

“…( 56 ) LRP6 mutations elsewhere than affecting the first β‐propeller have also been associated with early‐onset atherosclerosis. ( 57 , 58 , 59 ) Of interest, Pickering and colleagues ( 60 ) in 2021 reported a young woman with skeletal changes resembling Camurati‐Engelmann disease (OMIM #131300), ( 30 ) who carried a novel LRP6 defect that would compromise the second β‐propeller, and Puente and colleagues ( 61 ) in 2022 reported familial low bone mineral density associated with a mutation in the second propeller region. These LRP6 ‐associated disorders did not seem present in the family with LRP6 HBM we studied herein.…”