Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Area of Science:

• Genetics
• Biochemistry
• Neurology

Background:

• Biallelic pathogenic variants in the PNPLA6 gene are linked to diverse disorders including gait disturbance, visual impairment, hypopituitarism, and hair anomalies.
• The precise role of neuropathy target esterase (NTE) dysfunction in these varied phenotypes remains incompletely understood.

Purpose of the Study:

• To systematically review PNPLA6 variants and establish a functional assay for variant classification.
• To investigate the genotype:activity:phenotype relationship in PNPLA6-associated disorders.
• To develop a preclinical model for therapeutic development.

Main Methods:

• Systematic evidence-based review of 23 new and 95 reported patients with PNPLA6 variants.
• Measurement of esterase activity for 46 disease-associated and 20 common PNPLA6 variants.
• In vivo studies using an allelic mouse series.

Main Results:

• Missense variants were identified as key drivers of disease pathogenesis.
• A robust functional assay was established, reclassifying 36 variants as pathogenic and 10 as likely pathogenic.
• An inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy was observed, consistent in mouse models.

Conclusions:

• PNPLA6 disorders represent a continuous spectrum of phenotypes driven by an NTE genotype:activity:phenotype relationship, not merely allelic variations.
• The established relationship and preclinical model provide a foundation for future therapeutic trials targeting NTE.