Protein informatics combined with multiple data sources enriches the clinical characterization of novel TRPV4 variant...

Area of Science:

• Genetics and Molecular Biology
• Biophysics
• Clinical Medicine

Background:

• Transient receptor potential cation channel subfamily V member 4 (TRPV4) is a Ca2+-permeable ion channel activated by various stimuli.
• Pathogenic variants in TRPV4 are linked to skeletal dysplasias and neuromuscular disorders, but genotype-phenotype correlations are often unclear.
• TRPV4 is expressed in osteoclasts, chondrocytes, and sensory neurons, indicating its diverse physiological roles.

Observation:

• A novel TRPV4 variant, c.2401A>G (p.K801E), was identified in a proband and her family members.
• The proband, her father, and her daughter presented with overlapping symptoms consistent with TRPV4-associated skeletal dysplasia.
• Genomic exome analysis and clinical studies were performed to investigate the variant's impact.

Findings:

• Protein informatics and molecular modeling confirmed the pathogenicity of the novel c.2401A>G TRPV4 variant.
• The identified variant demonstrated complex genotype-phenotype correlations within the affected family.
• Comparative analysis of the proband's phenotype with known TRPV4-associated skeletal dysplasias was conducted.

Implications:

• This study provides a comprehensive perspective on the disease and prognosis associated with the unique TRPV4 variant.
• Understanding the pathogenicity of novel TRPV4 variants is crucial for accurate diagnosis and genetic counseling.
• Further research into TRPV4 variants can elucidate the pathogenesis of skeletal dysplasias and neuromuscular disorders.