Unexpected pathogenic mechanism of a novel mutation in the coding sequence of SPG4 (spastin).
basic_science · Level V
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Abstract
The authors report a nucleotide substitution (c.1216A>G) in SPG4 (spastin) causing hereditary spastic paraplegia. This apparent missense mutation in the ATPase domain confers aberrant, in-frame splicing and results in destabilization of mutated transcript. Mutated protein is deficient in microtubule-severing activity but, unlike neighboring mutations, shows regular subcellular localization. The authors' data point to haploinsufficiency rather than a dominant negative effect as the disease-causing mechanism for this mutation.
Medical subject headings
- Adenosine Triphosphatases
- Mutation, Missense
- Spastic Paraplegia, Hereditary