NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity

Area of Science:

• Genetics
• Neuroscience
• Biochemistry

Background:

• Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) is an autosomal recessive disorder.
• Hallmarks include global developmental delay, severe intellectual disability, microcephaly, cortical atrophy, cerebellar hypoplasia, and delayed myelination.

Purpose of the Study:

• To describe the clinical features of two siblings with NMIHBA.
• To investigate the molecular mechanisms underlying NMIHBA caused by PRUNE1 variants.
• To explore the role of PRUNE1 exopolyphosphatase activity in neurodevelopment.

Main Methods:

• Clinical description of affected siblings with compound heterozygous PRUNE1 variants.
• Biochemical characterization of PRUNE1 missense variants.
• Analysis of Prune1 function in a mouse model.

Main Results:

• Identified compound heterozygous variants c.383G>A (p.Arg128Gln) and c.520G>T (p.Gly174*) in PRUNE1 in affected siblings.
• Demonstrated that missense variants in the DHH motif destabilize protein structure and/or reduce exopolyphosphatase activity.
• Showed that genetic ablation of Prune1 leads to midgestational lethality in mice with developmental defects.

Conclusions:

• NMIHBA is associated with hypomorphic PRUNE1 variants in humans.
• PRUNE1 exopolyphosphatase activity is critical for normal neurodevelopment.
• The study highlights the role of PRUNE1 in embryonic growth and vascular development.