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Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third
Yentl Huybrechts1, Eveline Boudin1, Gretl Hendrickx1
1Center of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium.
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.
Insights
Sclerosteosis, a high bone mass disorder, can result from novel LRP4 gene variants in the first β-propeller domain. These variants impair sclerostin
Area of Science:
- Genetics
- Molecular Biology
- Endocrinology
Background:
- Sclerosteosis is a high bone mass disorder linked to sclerostin or LRP4 gene variants.
- Sclerostin and LRP4 form a complex inhibiting canonical WNT signaling, crucial for bone formation.
- Previously, all identified LRP4 pathogenic variants were in the third β-propeller domain, vital for sclerostin interaction.
Observation:
- A patient with sclerosteosis presented compound heterozygous variants in LRP4: a known p.Arg1170Gln and a novel p.Arg632His.
- The novel p.Arg632His variant is located in the first β-propeller domain of LRP4, typically involved in agrin interaction.
- Luciferase reporter assays were used to assess the functional impact of these variants.
Findings:
- Both p.Arg1170Gln and the novel p.Arg632His variants in LRP4 were shown to reduce sclerostin's inhibitory effect on canonical WNT signaling.
- This indicates that variants in the first β-propeller domain of LRP4 can disrupt WNT pathway regulation.
Implications:
- This study identifies the first pathogenic variant in the first β-propeller domain of LRP4 associated with sclerosteosis.
- The findings expand the known mutational spectrum for sclerosteosis.
- This broadens understanding of LRP4's role in bone mass regulation and WNT signaling pathways.
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