Phenotypic and molecular characterization of a recurrent SPTAN1 mutation causing SPG91

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Spectrins are essential cytoskeleton proteins in metazoan cells.
• Alpha-II spectrin (encoded by SPTAN1) organizes the axonal cytoskeleton.
• SPTAN1 mutations cause inherited neurological disorders like hereditary spastic paraplegia (HSP).

Purpose of the Study:

• To investigate the genotype-phenotype correlation of SPTAN1 mutations in SPG91.
• To analyze the molecular effects of the SPTAN1 p.Arg19Trp variant.

Main Methods:

• Clinical case study of two SPG91 patients with SPTAN1 c.55C>T (p.Arg19Trp) mutation.
• Literature review and meta-analysis of reported SPG91 cases.
• Computational simulations to predict protein stability effects.

Main Results:

• The SPTAN1 p.Arg19Trp mutation is associated with SPG91, presenting with lower limb spasticity and polyneuropathy.
• Combined analysis revealed 35% sensory-motor polyneuropathy and 30% cerebellar ataxia in patients with this mutation.
• Computational models indicated the variant perturbs alpha-II/beta spectrin heterotetramerization stability without destabilizing the alpha-II spectrin tetramerization domain.

Conclusions:

• Genotype-phenotype correlations for SPTAN1 mutations provide insights into neurological diseases.
• Understanding the molecular impact of SPTAN1 variants is crucial for diagnosing and potentially treating spectrin-related disorders.