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General Information
Name
spastic paraplegia 4
FlyBase ID
FBhh0000036
Disease Ontology Term
Parent Disease
Overview

This report describes spastic paraplegia 4 (SPG4), which is a subtype of spastic paraplegia; SPG4 exhibits autosomal dominant inheritance. The human gene implicated in this disease is SPAST (Spastin), which encodes an ATP-dependent microtubule severing protein and shares sequence similarity with the N-terminal MIT (microtubule interacting and trafficking) domain of the protein associated with SPG20. There is a single fly ortholog, spas, for which classical amorphic and loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

Multiple different UAS constructs of the human Hsap\SPAST gene have been introduced into flies, including wild-type and genes carrying mutational lesions implicated in SPG4. Heterologous rescue (functional complementation) of some aspects of the phenotype of a Dmel\spas null mutation has been demonstrated, including an increase in survival to adulthood. Variant(s) implicated in human disease tested (as transgenic human gene, SPAST): the K388R, C448Y, S44L, P45Q, and R431(term) variant forms of the human gene have been introduced into flies.

Variant(s) implicated in human disease tested (as analogous mutation in fly gene): K467R (in isoform used) in the fly spas gene (corresponds to K388R in the human SPAST gene).

Variant(s) implicated in human disease tested (as analogous mutation in fly spas gene in Drosophila cell culture; FBrf0187332): designated D655N (corresponds to D555N in the human SPAST gene); designated K488R (corresponds to K388R in the human SPAST gene); designated E542A (corresponds to E442A in the human SPAST gene); designated S462C (corresponds to S362C in the human SPAST gene).

Amorphic (null) mutations of spas are semi-lethal; animals that survive to adulthood die within a week of eclosion and exhibit locomotor defects; larvae exhibit neural defects. Genetic interactions have been characterized, using the amorphic spas mutant phenotypes. Physical interaction(s) of the Dmel\spas protein product have been described; see below and in the gene report for spas.

[updated Aug. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: spastic paraplegia
Symptoms and phenotype

The hereditary spastic paraplegias (SPG, HSP) are a large group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and whether the primary symptoms occur in isolation ('uncomplicated SPG') or with other neurologic abnormalities ('complicated SPG'). [from OMIM:182600; 15.06.29]

Specific Disease Summary: spastic paraplegia 4
OMIM report

[SPASTIC PARAPLEGIA 4, AUTOSOMAL DOMINANT; SPG4](https://omim.org/entry/182601)

Human gene(s) implicated

[SPASTIN; SPAST](https://omim.org/entry/604277)

Symptoms and phenotype

See general description of spastic paraplegia above. The age of onset and the severity of symptoms both vary widely in cases of SPG4. [from OMIM:182601; 15.06.30]

SPG4 is the most common form of autosomal dominant HSP, accounting for approximately 45% of cases. Affected individuals have slowly progressive muscle weakness and spasticity. In rare cases, some individuals may have a complex form associated with seizures, ataxia, memory impairment, cognitive decline and dementia. Hand tremor and upper limb spasticity have also been reported. Onset can range from infancy to older adulthood. [from NORD: Hereditary Spastic Paraplegia; 2016.09.02]

Genetics

SPG4 is inherited as an autosomal dominant; it is caused by mutations in the SPAST (spastin) gene. SPG4 is the most common form of autosomal dominant hereditary SPG, comprising up to 45% of cases (Svenson et al., 2001, pubmed:11309678; Crippa et al., 2006, pubmed:16682546). [from OMIM:182601; 15.06.30]

Cellular phenotype and pathology
Molecular information

SPAST encodes an ATP-dependent microtubule severing protein and is a member of the AAA ATPase family. Microtubule severing may promote reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. SPAST is required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and for completion of the abscission stage of cytokinesis, and may also play a role in axon growth and the formation of axonal branches. [UniProtKB accession Q9UBP0; RefSeq accession NM_014946]

The SPAST gene shares sequence similarity with the N-terminal region of SPG20 (spartin, causative gene of SPG20). [from OMIM:607111; 15.07.01]

External links
Disease synonyms
SPG4
familial spastic paraplegia 2
FSP2
spastic paraplegia
SPG
hereditary spastic paraplegia
HSP
AD-HSP
autosomal dominant hereditary spastic paraplegia
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

One to one: 1 human to 1 Drosophila; additional more distantly related gene(s) in both species.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    spastin (spas) encodes a member of the AAA ATPase family that assembles into hexamers and severs microtubules along their lengths. The microtubule binding and severing activities of the product of spas are dependent upon tubulin glutamylation levels. Its proposed roles include mitosis, axon transport, synapse formation, dendrite arborization, organelle tubulation, and lipid droplet metabolism. [Date last reviewed: 2018-11-08]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human SPAST (1 Drosophila to 1 human); additional more distantly related gene(s) in both species. Dmel\spas shares 44% identity and 55% similarity with human SPAST.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (3 groups)
      protein-protein
      Interacting group
      Assay
      References
      cosedimentation, molecular weight, electron microscopy
      pull down, anti tag western blot
      Alleles Reported to Model Human Disease (Disease Ontology) (13 alleles)
      Models Based on Experimental Evidence ( 6 )
      Modifiers Based on Experimental Evidence ( 2 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 5 )
      Modifiers Based on Experimental Evidence ( 3 )
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      Delta2-3 transposase
      amorphic allele - molecular evidence
      Delta2-3 transposase
      Delta2-3 transposase
      References (30)