Phosphoinositide Metabolism: Biochemistry, Physiology and Genetic Disorders

Area of Science:

• Cell Biology
• Biochemistry
• Genetics

Background:

• Phosphoinositides (PItds) are key regulators of cellular processes, derived from phosphatidylinositol.
• Over 50 enzymes control the PItd network, enabling precise spatial and temporal regulation of PItd levels.
• PItds are crucial for organelle identity, membrane trafficking, signaling pathways, and molecular transport.

Purpose of the Study:

• To review the diverse roles of phosphoinositides in cell biology.
• To summarize the clinical spectrum and genetic basis of phosphoinositide metabolism disorders.
• To highlight challenges in diagnosing and treating these genetic conditions.

Main Methods:

• Literature review of phosphoinositide metabolism and associated genetic disorders.
• Analysis of clinical presentations and genetic variants in 34 genes.
• Discussion of diagnostic approaches and therapeutic development challenges.

Main Results:

• PItd signatures define organelle identity and regulate trafficking, signaling, and membrane contact sites.
• Genetic variants in 34 genes lead to at least 41 distinct monogenic disorders.
• These disorders manifest with multisystemic effects, frequently involving the nervous system, muscles, and immune system.

Conclusions:

• Genetic disorders of phosphoinositide metabolism represent a broad and expanding category of inborn errors.
• Clinical diagnosis is often challenging, necessitating broad molecular testing.
• Further research is needed for improved clinical documentation, biochemical diagnostics, and targeted therapies.