Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

Area of Science:

• Neurogenetics
• Molecular Biology
• Developmental Biology

Background:

• GEMIN5 is an RNA-binding protein crucial for the survival motor neuron (SMN) complex assembly and small nuclear ribonucleoprotein (snRNP) biogenesis.
• snRNPs are essential components of spliceosomes, fundamental for RNA processing.
• Dysfunctional snRNP formation is implicated in various genetic disorders.

Purpose of the Study:

• To investigate the role of GEMIN5 variants in a cohort of patients with neurodevelopmental disorders.
• To elucidate the molecular mechanisms underlying GEMIN5-associated neurodevelopmental conditions.
• To establish a genotype-phenotype correlation for GEMIN5 mutations.

Main Methods:

• Genetic analysis of 30 individuals from 22 families with developmental delay, hypotonia, and cerebellar ataxia.
• Functional studies using patient-derived induced pluripotent stem cell (iPSC)-derived neurons to assess GEMIN5 protein behavior and snRNP assembly.
• In vivo studies utilizing the Drosophila melanogaster model by knocking down the GEMIN5 homolog, rigor mortis.
• Comparative transcriptomic analysis between GEMIN5 and Spinal Muscular Atrophy (SMA) patient neurons.

Main Results:

• Identified biallelic variants in the GEMIN5 gene in 30 affected individuals.
• Demonstrated that GEMIN5 mutations disrupt protein localization, stability, and expression in patient iPSC-derived neurons, suggesting a loss-of-function.
• Observed impaired snRNP complex assembly in patient-derived neurons.
• Showcased developmental defects, motor dysfunction, and reduced lifespan in flies with GEMIN5 homolog knockdown.
• Highlighted distinct molecular pathways affected by GEMIN5 variants compared to SMA.

Conclusions:

• Pathogenic GEMIN5 variants cause a novel neurodevelopmental disorder characterized by developmental delay, hypotonia, and cerebellar ataxia.
• GEMIN5 mutations disrupt snRNP biogenesis and cellular processes, leading to neurodevelopmental deficits.
• The findings provide insights into the molecular pathogenesis of GEMIN5-related disorders and suggest potential therapeutic targets.