Clinical Report: Differentiating Pathogenic from Benign TRPV4 Variants
Overview
This study integrates clinical data with structural and cellular analyses to distinguish pathogenic gain-of-function TRPV4 variants from benign ones. It identifies specific mutation clusters within TRPV4 domains that correlate with disease phenotypes and functional channel alterations.
Background
Mutations in TRPV4 cause diverse hereditary neuropathies and skeletal dysplasias characterized by variable clinical features including motor and sensory deficits, vocal cord weakness, and skeletal abnormalities. TRPV4 is a mechanosensitive ion channel with key domains such as the ankyrin repeat domain (ARD) and intrinsically disordered region (IDR) that regulate channel function and protein interactions. Disease-causing mutations typically result in gain of ion channel function leading to increased intracellular calcium and cellular toxicity, which can be rescued by TRPV4 antagonists in models. However, many TRPV4 variants detected by sequencing remain of uncertain pathogenicity, necessitating integrated functional and clinical evaluation.
Gain of function, altered membrane lipid interactions
Similar clinical features as ARD gain-of-function variants
Transmembrane domain and other IDR regions
No gain of function, likely benign
Late-onset, sensory-predominant disease
Key Findings
Gain-of-function TRPV4 mutations cluster in the ankyrin repeat domain at charged residues critical for RhoA interaction.
A distinct cluster of gain-of-function variants in the intracellular intrinsically disordered region may cause toxicity via altered membrane lipid interactions.
Variants in the transmembrane domain and other IDR regions generally do not cause gain of function and are likely benign.
Clinical phenotypes of gain-of-function mutations include congenital onset, vocal cord weakness, and predominantly motor neuropathy.
Likely benign variants are associated with later disease onset and sensory-predominant neuropathy.
Functional assays including ion channel activity, cytotoxicity, and protein interactions provide a framework for pathogenicity assessment.
Clinical Implications
This integrated approach enables more accurate classification of TRPV4 variants, guiding diagnosis and prognosis in patients with neuromuscular and skeletal disorders. Identification of gain-of-function mutations supports the potential use of TRPV4 antagonists as targeted therapies. Clinicians should consider domain-specific mutation effects when evaluating TRPV4-related disease presentations.
Conclusion
Combining clinical phenotyping with structural and functional analyses effectively differentiates pathogenic TRPV4 variants from benign ones, informing patient selection for emerging TRPV4-targeted treatments.
References
Original Article 2024 -- Integrative Clinical, Structural, and Cellular Analyses Differentiate Pathogenic from Benign Variants of TRPV4
by Sarah H Berth, Linh Vo, Do Hoon Kwon, Tiffany Grider, Yasmine S Damayanti, Gage Kosmanopoulos, Andrew Fox, Alexander R Lau, Patrice Carr, Jack K Donohue, Maya Hoke, Simone Thomas, Chafic Karam, Alex J Fay, Ethan Meltzer, Thomas O Crawford, Rachelle Gaudet, Michael E Shy, Ute A Hellmich, Seok-Yong Lee, Charlotte J Sumner, Brett A McCray
