by Genomic Press

Structural effects of a single frameshift homozygous nucleotide deletion in the SPAG9/JIP4 gene. Representation of the three-dimensional model in tapes. (A) Region of the SPAG9wt protein after position 914 (in yellow and orange). (B) SPAG9wt and SPAG9Tyr914Ter (violet) proteins. There was no alignment of the structures. The effect of the charges of the amino acids was lost, affecting their folding and inducing changes in angles that alter the functional interaction. Credit: Natalia Acosta-Baena

Researchers from the University of Antioquia have identified a new genetic syndrome that bridges the gap between neurodevelopmental disorders and neurodegenerative diseases. The study, published in Genomic Psychiatry, details a homozygous mutation in the SPAG9 gene that leads to a complex neurological phenotype characterized by intellectual disability, speech delays, and progressive cognitive decline.

Dr. Natalia Acosta-Baena, the study's lead author, explains, "This discovery is significant because it provides a unique window into how a single genetic alteration can affect both brain development and long-term neurological health. It's a rare opportunity to study the intersection of these two critical areas of neuroscience."

The research team followed a Colombian family for over a decade, observing three siblings affected by the syndrome. Their comprehensive approach included genetic analysis, neuroimaging, and long-term clinical observation, providing a rich dataset that offers insights into the syndrome's progression over time.

Key findings of the study include:

• Identification of a homozygous deletion in the SPAG9 gene (c.2742del, p.Tyr914Ter) as the cause of the syndrome.

• Detailed clinical characterization of the affected individuals, revealing a spectrum of symptoms including intellectual disability, cataracts, and cerebellar signs.

• Evidence of progressive cognitive decline, suggesting a neurodegenerative component to the syndrome.

• Neuroimaging results showing heterogeneous brain abnormalities, including microcephaly, hippocampal malrotation, changes in corpus callosum structure, iron deposition, and cerebral and cerebellar atrophy.

Dr. Carlos Andrés Villegas-Lanau, senior author of the study, highlights the broader implications of their findings, "This syndrome provides a unique model for studying how disruptions in cellular transport mechanisms can lead to both developmental and degenerative brain conditions. It could have far-reaching implications for our understanding of more common neurological disorders."

The SPAG9 gene, previously unstudied in the context of brain disorders, is known to play a crucial role in cellular transport processes. The researchers hypothesize that the mutation disrupts the retrograde axonal transport system, a critical mechanism for maintaining neuronal health and function.

"Our findings suggest that SPAG9 is essential for normal brain development and long-term neuronal survival," adds Dr. Acosta-Baena. "This could open new avenues for therapeutic interventions not just for this rare syndrome, but potentially for a broader range of neurological conditions."

The study's long-term follow-up of affected individuals provides valuable insights into the natural history of the syndrome, showing how symptoms evolve from childhood into adulthood. This longitudinal perspective is rare in genetic studies and offers a unique opportunity to understand the lifelong impact of the mutation.

The research team emphasizes the need for further studies to fully elucidate the mechanisms by which SPAG9 mutation leads to neurological dysfunction. They are currently exploring potential therapeutic approaches based on their findings.

More information: Acosta-Baena, N. et al. A novel neurodevelopmental-neurodegenerative syndrome that cosegregates with a homozygous SPAG9/JIP4 stop-codon deletion, Genomic Psychiatry (2024). DOI: 10.61373/gp024a.0052. gp.genomicpress.com/wp-content … costa-Baena-2004.pdf

Provided by Genomic Press