Pyle disease - Functional validation of disease-causing missense variants in SFRP4/sFRP4

Area of Science:

• Genetics
• Molecular Biology
• Bone Metabolism

Background:

• Pyle disease is a rare autosomal recessive bone dysplasia characterized by bone fragility and modeling defects.
• Bi-allelic truncating variants in SFRP4 are the primary known cause of Pyle disease.
• SFRP4 encodes secreted Frizzled related protein 4 (sFRP4), a WNT signaling inhibitor.

Purpose of the Study:

• To investigate the role of SFRP4 missense variants in Pyle disease.
• To functionally characterize a novel SFRP4 homozygous missense variant.
• To expand the understanding of the molecular basis of Pyle disease.

Main Methods:

• Clinical and radiographic assessment of a patient with Pyle disease.
• Genetic testing to identify variants in SFRP4.
• Luciferase reporter assays to assess WNT/β-catenin signaling inhibition by sFRP4 variants.

Main Results:

• A novel homozygous missense variant (c.314G>C, p.(Arg105Pro)) in the WNT-binding domain of SFRP4 was identified in a patient with Pyle disease.
• The identified p.(Arg105Pro) variant, along with previously reported missense variants (p.(Ala54Asp), p.(Cys125Ser)), impaired sFRP4's inhibitory effect on WNT/β-catenin signaling.
• Functional studies confirmed that missense variants can be as detrimental as truncating variants in SFRP4.

Conclusions:

• Missense variants in SFRP4 can cause Pyle disease by impairing WNT signaling inhibition.
• This finding expands the mutational spectrum of Pyle disease and aids in diagnosing affected families.
• The WNT-binding domain of sFRP4 is critical for its function as a WNT signaling inhibitor.