PHIP gene variants with protein modeling, interactions, and clinical phenotypes

Area of Science:

• Genetics
• Molecular Biology
• Clinical Medicine

Background:

• Chung-Jansen syndrome is a rare genetic disorder characterized by dysmorphic features, cognitive impairment, behavioral issues, and early-onset obesity.
• Variants in the pleckstrin homology domain-interacting protein (PHIP) gene have been linked to the syndrome's clinical presentation.
• Understanding the spectrum and impact of PHIP variants is crucial for diagnosis and management.

Purpose of the Study:

• To systematically review and summarize reported PHIP variants associated with Chung-Jansen syndrome.
• To describe a novel patient with a rare PHIP variant and compare their phenotype with previously reported cases.
• To analyze the structural and functional consequences of PHIP variants on protein interactions and disease pathology.

Main Methods:

• Systematic literature review of patients with PHIP variants.
• Clinical data compilation and variant frequency analysis.
• Structural protein modeling and prediction of protein-protein interactions.

Main Results:

• 35 patients with unique PHIP variants were identified and their clinical data summarized.
• A novel patient with a five base pair deletion in PHIP (I307fs) presented with Chung-Jansen syndrome features.
• Structural modeling suggested altered protein stability and interactions, potentially involving POMC, contributing to obesity and other comorbidities.

Conclusions:

• PHIP variants are definitively linked to Chung-Jansen syndrome, with diverse mutation types impacting clinical presentation.
• The novel I307fs variant and its potential functional consequences highlight the importance of precise genetic analysis.
• Protein-protein interactions involving POMC suggest a molecular basis for obesity and other associated disorders in PHIP-related conditions.