SPAST

Chr 2AD

spastin

Also known as: ADPSP, FSP2, SPG4

NCBI Gene: 6683 ENSG00000021574 UniProt: Q9UBP0 OMIM: 604277

The protein functions as a microtubule-severing enzyme that regulates microtubule abundance, mobility, and plus-end distribution, and is a member of the AAA ATPase family involved in diverse cellular processes including membrane trafficking and intracellular motility. Loss-of-function mutations cause autosomal dominant spastic paraplegia 4, which is the most common form of hereditary spastic paraplegia. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the disease mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.221 OMIM phenotype

Clinical Summary— SPAST

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.22LOEUF

pLI 0.999

Z-score 4.97

OE 0.09 (0.04–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.24Z-score

OE missense 0.81 (0.73–0.90)

279 obs / 343.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.22)

0≤0.351.4

Missense OE?0.81 (0.73–0.90)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 3 / 34.6Missense obs/exp: 279 / 343.9Syn Z: -2.36

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSPAST-related spastic paraplegiaLOFAD

strongSPAST-related developmental disorderOTHERAD

This gene — mechanism propensity

0.4983th %ile

GOF

0.4776th %ile

LOF

0.68top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.22 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

Literature Evidence

GOFMutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of hereditary spastic paraplegia (HSP). Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possi1

LOFClassical mutations in the most frequent HSP gene SPAST (spastin protein) act through haploinsufficiency by abolishing the activity of a C-terminal ATPase domain or by interfering with expression from the affected allele.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References