SORD, the sorbitol dehydrogenase gene, encodes an enzyme that converts sorbitol into fructose in the two-step polyol pathway. This pathway has implications in diabetic neuropathy, highlighting the gene's biological importance in metabolic and neurological contexts [1].

Biallelic mutations in SORD are a frequent cause of recessive hereditary neuropathy. In patient-derived fibroblasts, there is a complete loss of SORD protein and increased intracellular sorbitol, with dramatically increased serum fasting sorbitol levels [1]. In Drosophila, loss of SORD orthologs causes synaptic degeneration and progressive motor impairment [1]. Sord knockout (KO) Sprague Dawley rats develop a motor-predominant peripheral neuropathy closely resembling the human phenotype. These rats have increased sorbitol levels in serum, CSF, and peripheral nerve, along with signs of axonal degeneration and abnormal gait, slowed motor nerve conduction velocities, and specific myelin sheath changes mainly affecting myelinated motor axons [2,3].

In conclusion, SORD is crucial in the polyol pathway for regulating sorbitol levels. Model-based research, especially using Sord KO rat models, has revealed its significant role in hereditary neuropathy. Understanding SORD's function may contribute to better comprehension of the pathophysiology of related diseases and potentially develop treatment strategies for neuropathy and diabetes-related complications [1,2,3].

References:

1. Cortese, Andrea, Zhu, Yi, Rebelo, Adriana P, Zhai, R Grace, Zuchner, Stephan. 2020. Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes. In Nature genetics, 52, 473-481. doi:10.1038/s41588-020-0615-4. https://pubmed.ncbi.nlm.nih.gov/32367058/

2. Rebelo, Adriana P, Abad, Clemer, Dohrn, Maike F, Walz, Katherina, Zuchner, Stephan. . SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights. In Brain : a journal of neurology, 147, 3131-3143. doi:10.1093/brain/awae079. https://pubmed.ncbi.nlm.nih.gov/38538210/

3. Rebelo, Adriana P, Abad, Clemer, Dohrn, Maike F, Walz, Katherina, Zuchner, Stephan. 2023. Sord deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.12.05.570001. https://pubmed.ncbi.nlm.nih.gov/38106042/