Abstract
Sclerosteosis is a high bone mass disorder, caused by pathogenic variants in the genes encoding sclerostin or LRP4. Both proteins form a complex that strongly inhibits canonical WNT signaling activity, a pathway of major importance in bone formation. So far, all reported disease-causing variants are located in the third β-propeller domain of LRP4, which is essential for the interaction with sclerostin. Here, we report the identification of two compound heterozygous variants, a known p.Arg1170Gln and a novel p.Arg632His variant, in a patient with a sclerosteosis phenotype. Interestingly, the novel variant is located in the first β-propeller domain, which is known to be indispensable for the interaction with agrin. However, using luciferase reporter assays, we demonstrated that both the p.Arg1170Gln and the p.Arg632His variant in LRP4 reduced the inhibitory capacity of sclerostin on canonical WNT signaling activity. In conclusion, this study is the first to demonstrate that a pathogenic variant in the first β-propeller domain of LRP4 can contribute to the development of sclerosteosis, which broadens the mutational spectrum of the disorder.
Highlights
Sclerosteosis is a high bone mass disorder, caused by pathogenic variants in the genes encoding sclerostin or LRP4
Our study shows the identification and functional investigation of two compound heterozygous variants in LRP4 in a Spanish sclerosteosis patient (Figure 3)
Functional investigation of both variants in parallel demonstrated that the presence of the p.Arg632His variant impaired the inhibitory capacity of sclerostin on canonical WNT signaling activity, similar to the p.Arg1170Gln variant (Figure 4)
Summary
Sclerosteosis is a high bone mass disorder, caused by pathogenic variants in the genes encoding sclerostin or LRP4. Both proteins form a complex that strongly inhibits canonical WNT signaling activity, a pathway of major importance in bone formation. Using luciferase reporter assays, we demonstrated that both the p.Arg1170Gln and the p.Arg632His variant in LRP4 reduced the inhibitory capacity of sclerostin on canonical WNT signaling activity. Studies demonstrated that LRP4 can interact with sclerostin, and facilitate the inhibitory actions of sclerostin on the canonical WNT signaling pathway, and, affect bone formation [8,10–12]. We and others were able to identify three sclerosteosis-causing variants in LRP4 (p.Trp1186Ser, p.Arg1170Trp, p.Arg1170Gln) [8,13,14] All these variants are located in the cavity of the third β-propeller domain [13,15]. The importance of the third β-propeller domain has been emphasized by the successful generation of two novel mouse models, the Lrp Arg1170Gln knock-in mouse and the Lrp
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