A newly discovered mutation in the SPAG9 gene may affect both neurodevelopment and neurodegeneration. The mutation, identified in three siblings, is linked to disruptions in brain structure and function, leading to speech delays, progressive cognitive decline, and intellectual disability. MRI scans revealed abnormalities such as microcephaly, malrotation of the hippocampus, and brain atrophy. This research not only deepens our understanding of how genetic mutations impact brain health but also opens potential avenues for future treatments targeting developmental and degenerative brain conditions.
Within each cell, various molecules are transported, a process essential for the cell to survive and thrive. In neurons, which are nerve cells, this transport is especially challenging because there is a long distance between the cell body (where the nucleus is) and the ends of the axons (the long “extensions” of neurons that transmit nerve signals).
In addition to distance, another challenge is that neurons need to deliver specific materials to specific locations, such as synapses, to ensure that communication between neurons works properly.
Neurons use a system called "axonal transport" to move various substances from one place to another. There are two main types of axonal transport:
Anterograde transport: This transports substances from the cell body to the end of the axon. This is done by proteins called kinesins, which transport molecules such as RNA, proteins, and other structures that are important for the neuron to continue functioning and communicating with other cells.
Retrograde transport: This transports substances from the end of the axon back to the cell body. This process is important for several functions, such as the breakdown of substances and nerve regeneration. This movement is done by proteins called dyneins.
Both of these types of transport require "motors" (proteins that help with transport) and "tracks" (called microtubules) to work properly. In addition, certain signaling pathways and protein modifications ensure that transport is efficient.
If something goes wrong in axonal transport, neuron function can be impaired, leading to problems such as disruption of communication between nerve cells and impaired plasticity (the ability to adapt and change). Many neurological diseases are related to problems in this transport.
Among several, a protein called JIP4 is important in retrograde transport. It is encoded by a gene called SPAG9 and is expressed in various parts of the nervous system. This protein is essential for brain development and for maintaining the long-term health of neurons.
In humans, SPAG9/JIP4 has been associated with the prognosis of different types of cancer but has never been associated with intellectual disability and/or complex neurodevelopmental phenotypes.
An article published in Genomic Psychiatry by researchers from the University of Antioquia describes three siblings who have a mutation in the SPAG9 gene, which affects the JIP4 protein. Case 1 is a boy, and Case 2 and Case 3 are girls who were born at term without complications and with normal weight.
A genetic sequencing test showed that they are homozygous with a mutant variant of the SPAG9 gene; deletions in this gene generate changes in the protein in terms of length and amino acid composition due to the lack of assembly of 407 amino acids. This mutation causes developmental delays, learning difficulties, and motor problems.
Over 10 years, the brothers also showed a progressive decline in cognitive functions, suggesting that the problem not only affects development but can also cause brain degeneration over time.
Table 2 summarizes the findings. The three siblings were classified as having moderate intellectual disability according to DSM-5 criteria, and all three had an IQ score of 45. doi: 10.61373/gp024a.0052
In addition, MRI scans showed changes in the brains of these individuals, such as a decrease in the size of a structure called the corpus callosum (responsible for connecting the two hemispheres of the brain) and abnormal accumulation of iron in some regions. Iron is the most abundant metal in neurons, and failures in its transport and storage are processes associated with neurodegenerative disorders.
It is interesting to explore these findings further, as they could provide clues to mechanisms that are not yet understood in dementia syndromes. These changes are linked to neurodegeneration, a process in which neurons deteriorate.
The Figure shows findings reported on brain MRI of the three siblings. (A) Comparison between the three cases according to 1. Measurements of the front-occipital diameter (FOD) and CC parameters (GT: Genu thickness, BT: Body thickness, IT: Isthmus thickness, ST: Splenium thickness) 2. The gradient of iron deposits in the putamen nucleus, from smallest to largest, with case 3 being the largest. 3. Cerebellum and fourth ventricle. (B) 1. Bilateral hippocampal malrotation (Case 1). 2. Agenesis of the septum pellucidum (Case 3).
Today, the three cases have an average age of 34 years and have been followed for more than 10 years with worsening cognitive and behavioral function that corroborated progressive cognitive deterioration.
“We have not found similar findings in the literature caused by dysfunction in the retrograde transport machinery or axonal transport in general, where cases with a progressive phenotype, with neurodevelopmental disease and subsequent central neurodegeneration phenotype, have been reported,” says Dr. Acosta-Baena, one of the authors of the study.
These findings suggest that the JIP4 protein is critical for both normal brain development and for protecting neurons against degeneration throughout life. The research also raises new questions about how axonal transport is involved in neurological and degenerative diseases.
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A novel neurodevelopmental-neurodegenerative syndrome that cosegregates with a homozygous SPAG9/JIP4 stop-codon deletion Natalia
Acosta-Baena et al.
Genomic Psychiatry (2024) 1, 1–12; doi: 10.61373/gp024a.0052
Abstract:
This report outlines the clinical features of a complex neurological phenotype shared by three siblings from a consanguineous family, characterized by intellectual disabilities, speech developmental delay, gait disturbance, cerebellar syndrome signs, cataracts, and dysmorphic features (square and coarse facial features, thick lips, deep palate, small and spaced teeth, low-set ears, strabismus, eyelid ptosis, and blond hair). Seizures and brain atrophy were later evident. In the cosegregation analysis, five family members and 12 family controls were studied by whole-exome and Sanger sequencing. The structural and functional effects of the protein were explored to define the mutated variant’s potential deleterious impairment. Neurological and neuropsychological follow-ups and brain magnetic resonance imaging (MRI) were performed. We identified a single frameshift homozygous nucleotide deletion in the SPAG9/JIP4 gene (NM_001130528.3): c.2742del (p. Tyr914Ter), causing a premature stop codon and truncating the protein and originating a possible loss of function. The variant cosegregated in affected individuals as an autosomal recessive trait. The in silico protein functional analyses indicate a potential loss of 66 phosphorylation and 29 posttranslational modification sites. Additionally, a mutated protein structure model shows a significant modification of the folding that very likely will compromise functional interactions. SPAG9/JIP4 is a dynein-dynactin motor adapter for retrograde axonal transport, regulating the constitutive movement of neurotrophic factor signaling and autophagy-lysosomal products. Under stress conditions, it can potentiate this transport by the p38 mitogen-activated protein kinases (p38MAPK) signaling cascade. Both functions could be associated with the disease mechanism, altering the axon’s development and growth, neuronal specification, dendrite formation, synaptogenesis, neuronal pruning, recycling neurotransmitters and finally, neuronal homeostasis—promising common mechanisms to be used with investigational molecules for neurodevelopmental diseases and neurodegeneration.
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