A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle...

Area of Science:

• Molecular biology
• Neurogenetics
• Cellular biology

Background:

• PPP1R21 is a co-factor for protein phosphatase 1 (PP1), crucial for cellular processes.
• Pathogenic variants in PPP1R21 are associated with neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (NEDHFBA).
• Impaired vesicular transport is a known pathomechanism in PPP1R21-related disorders.

Purpose of the Study:

• To investigate the proteomic signature of fibroblasts from the first NEDHFBA patient with a splice-site mutation in PPP1R21.
• To further elucidate the pathophysiological mechanisms underlying NEDHFBA.

Main Methods:

• Proteomic analysis of fibroblasts from an NEDHFBA patient.
• Functional studies investigating cellular processes.
• Analysis of protein aggregates, cellular fitness, and cytoskeletal architecture.

Main Results:

• Proteomic analysis revealed profound activation of the ubiquitin-proteasome system and presence of protein aggregates.
• Functional studies demonstrated an impact on cellular fitness and a link between proteolytic system activation and cytoskeletal architecture (e.g., actin, filopodia).
• Dysregulation of neurologically relevant proteins, including pro-survival proteins, was observed, potentially explaining the milder phenotype.

Conclusions:

• PPP1R21 mutations activate the ubiquitin-proteasome system and disrupt cytoskeletal organization, expanding the known pathomechanisms of NEDHFBA.
• The findings suggest a complex interplay between protein degradation pathways, cytoskeletal dynamics, and cellular stress response in this disorder.
• The observed molecular signature may correlate with the milder clinical presentation in the studied patient.