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SPG4

Chr 2

spastin

Also known as: ADPSP, FSP2, SPG4

NCBI Gene: 6683 UniProt: Q9UBP0

The protein is an ATP-dependent microtubule severing enzyme that cuts polyglutamylated microtubules and is critical for maintaining complex microtubule arrays in axons, cell division, and membrane trafficking between cellular compartments. Mutations cause spastic paraplegia 4, the most common form of autosomal dominant hereditary spastic paraplegia, which primarily affects the corticospinal tracts and lower extremities. This follows autosomal dominant inheritance with high penetrance but variable expressivity.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the AAA (ATPases associated with a variety of cellular activities) protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The use of alternative translational initiation sites in this gene results in a single transcript variant that can produce isoforms that differ in the length of their N-terminus and which thereby differ in the efficiency of their export from the nucleus to the cytoplasm. In addition, alternative splicing results in multiple transcript variants that encode isoforms that differ in other protein regions as well. One isoform of this gene has been shown to be a microtubule-severing enzyme that regulates microtubule abundance, mobility, and plus-end distribution. Mutations in this gene cause the most frequent form of autosomal dominant spastic paraplegia 4. [provided by RefSeq, May 2018]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtSpastic paraplegia 4, autosomal dominant

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

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LOEUF

LOF

Mechanism· G2P

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GeneReview available — SPG4