NIH Research Festival
Free sialic acid storage disorder (FSASD) is an autosomal recessive lysosomal storage disorder characterized by mutations in SLC17A5, resulting in sialin transporter deficiency and subsequent accumulation of free sialic acid in tissues and biological fluids. FSASD exists as a clinical spectrum, ranging from mild developmental delay with progressive neurodegeneration, to severe disease with infantile fatality. Given the lack of approved therapies, the development of a reliable animal model is crucial for advancing preclinical translational studies.
Utilizing CRISPR/Cpf1 genome editing, we generated the Slc17a5-R39C mouse model carrying the most prevalent SLC17A5 variant observed in FSASD patients. Extensive phenotyping was performed through biochemical, molecular, behavioral, and histological assays.
Homozygous Slc17a5-R39C animals exhibited increased perinatal lethality, with 25% dying within four weeks. Progressive neurodegeneration was evident, characterized by gait abnormalities, tremors, and discoordination. Neurological evaluation revealed significant ataxia and impaired motor performance. A significant proportion of mutant mice exhibited seizures. Urinary analysis demonstrated a five-fold increase in free sialic acid levels, establishing that the Slc17a5-R39C mouse faithfully replicates the biochemical hallmark of disease. Histological examination revealed hypomyelination in the corpus callosum, cerebellum, and spinal cord tracts, along with a reduction in Purkinje neurons in the cerebellum. Ongoing investigations aim to elucidate the spatiotemporal progression of these findings.
The Slc17a5-R39C mouse represents a valuable tool for investigating molecular mechanisms, particularly regarding neurodevelopmental aspects of FSASD. This model holds promise for identifying longitudinal biomarkers and determining optimal treatment windows, thus enabling the development of molecular and pharmacological interventions to slow or halt disease progression.
Scientific Focus Area: Genetics and Genomics
This page was last updated on Monday, September 25, 2023