De novo variants in MPP5 cause global developmental delay and behavioral changes

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Membrane Protein Palmitoylated 5 (MPP5) is crucial for cell polarity and survival.
• Cell polarity defects are linked to neurological disorders like autism and microcephaly.
• MPP5's role in human neurodevelopment and associated genetic variants were previously undescribed.

Purpose of the Study:

• To investigate the association between MPP5 de novo variants (DNV) and global developmental delay (GDD).
• To elucidate the underlying mechanisms of MPP5 DNV-related neurodevelopmental impairment using a murine model.

Main Methods:

• Identified and characterized three patients with heterozygous MPP5 DNV and GDD.
• Analyzed patient phenotypes, including developmental delays, behavioral changes, and MRI findings.
• Created a heterozygous conditional knockout (het CKO) murine model with CNS-specific Nestin-Cre drivers to study Mpp5 depletion in the developing brain.

Main Results:

• Patients with MPP5 DNV exhibited GDD, language delay/regression, and behavioral changes.
• Murine models showed Mpp5 depletion resulted in microcephaly, reduced cerebellar volume, and cortical thinning.
• MPP5 depletion in mice led to decreased ependymal cells, impaired progenitor pool maintenance, increased apoptosis, and behavioral abnormalities.

Conclusions:

• MPP5 DNV are associated with GDD, behavioral abnormalities, and language regression in humans.
• MPP5 is essential for maintaining progenitor pools and regulating cell death during neurogenesis.
• Altered neurogenesis, characterized by increased cell death and skewed cellular composition, likely underlies the neurodevelopmental deficits observed in MPP5-related disorders.