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00:06
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
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Loss of Function SPTAN1 Variants Result in Ataxia and Intellectual Disability
Po-Nien Lu1, Chandler Melton2,3, Barbara Dupont1
1Greenwood Genetic Center, Greenwood, South Carolina, USA.
Clinical Genetics
|February 23, 2025
Summary
Loss-of-function variants in SPTAN1 cause a spectrum of neurodevelopmental disorders, including early infantile epileptic encephalopathy. D-aspartate supplementation may improve motor function in affected individuals.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Mutations in SPTAN1 are linked to autosomal dominant early infantile epileptic encephalopathy 5, characterized by early seizures and severe intellectual disability.
- Recent findings suggest a broader clinical spectrum for SPTAN1-related disorders, encompassing later-onset seizures and milder developmental delays.
Purpose of the Study:
- To investigate the functional consequences of novel SPTAN1 variants.
- To explore the genotype-phenotype correlations in patients with SPTAN1 loss-of-function variants.
- To identify potential therapeutic strategies for SPTAN1-associated motor dysfunction.
Main Methods:
- Analysis of two patients with SPTAN1 loss-of-function variants (homozygous p.(Gln1448Pro) and heterozygous p.(Asn1839del)).
- Ectopic expression of wild-type and variant sptan1 in zebrafish to assess protein function.
- Evaluation of Sptan1 protein abundance, localization in axons, and voltage-gated sodium channel localization.
- Behavioral analysis in zebrafish, including assessment of motility after D-aspartate supplementation.
Main Results:
- Both identified SPTAN1 variants resulted in loss-of-function alleles, with p.(Gln1448Pro) likely being hypomorphic.
- Variant Sptan1 proteins showed reduced abundance and abnormal localization in developing axons.
- The p.(Gln1448Pro) variant failed to restore voltage-gated sodium channel localization in sptan1-null axons.
- D-aspartate supplementation improved motility in sptan1-null zebrafish.
Conclusions:
- Loss-of-function variants in SPTAN1 contribute to a range of neurodevelopmental phenotypes, including ataxia, intellectual disability, and seizures.
- SPTAN1 variants impair axonal function, potentially through disruption of voltage-gated sodium channel localization.
- D-aspartate represents a potential therapeutic avenue for motor deficits associated with SPTAN1 dysfunction.
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