Loss of PIGK function causes severe infantile encephalopathy and extensive neuronal apoptosis

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• The PIGK gene is crucial for glycosylphosphatidylinositol (GPI) transamidase activity and has been linked to inherited GPI deficiency disorders (IGDs).
• The specific impact of PIGK on neurodevelopment remains largely unknown due to disease rarity and limited in vivo studies.

Purpose of the Study:

• To investigate the role of PIGK in neurodevelopment using patient-derived variants.
• To establish in vivo models for studying PIGK-related neurodevelopmental defects.

Main Methods:

• Genetic analysis of two patients with severe neurodevelopmental disorders identified novel compound heterozygous PIGK variants.
• Construction of Pigk knock-down zebrafish and knock-in mouse models to assess embryonic and neuronal development.
• Assessment of PIGK protein levels, cell surface GPI-anchored proteins (GPI-APs), and developmental phenotypes in models.

Main Results:

• Patients exhibited profound global developmental delay, hypotonia, seizures, and progressive brain atrophy.
• PIGK variants significantly reduced PIGK protein and cell surface GPI-AP expression.
• Pigk knock-down zebrafish showed severe developmental abnormalities, including microphthalmia, craniofacial deformities, and spinal curvature.
• Pigk knock-in mice carrying patient-homologous variants exhibited complete embryonic lethality, indicating critical roles for PIGK during development.

Conclusions:

• PIGK is essential for embryonic and neuronal development, with loss-of-function mutations leading to severe neurodevelopmental phenotypes.
• This study provides in vivo evidence supporting PIGK's critical role and establishes models for further mechanistic investigations.
• Findings offer a foundation for understanding the pathological mechanisms underlying PIGK-related neurodevelopmental disorders.