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General Information
Name
spastic paraplegia 3A
FlyBase ID
FBhh0000392
Disease Ontology Term
Parent Disease
Overview

This report describes spastic paraplegia 3A (SPG3A), which is a subtype of spastic paraplegia; it is an autosomal dominant form of the disease. The human gene implicated in this disease is Atlastin-1 (ATL1), which encodes a dynamin-related GTPase that plays a role in formation of the tubular endoplasmic reticulum (ER) network and in axon elongation in neurons. There is a single fly ortholog, atl, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\atl is orthologous to three other genes in human, ATL2, ATL3, and RNF112. The human ATL1 gene is also implicated in a form of hereditary sensory neuropathy (OMIM:613708).

The human ATL1 gene has not been introduced into flies.

Animals homozygous for a loss-of-function mutation of Dmel\atl die in late pupal stages; larva exhibit defects in neuroanatomy and neurophysiology. In homozygous third instar larvae, ER fragmentation is observed in motor neuron nerve terminals. Physical and genetic interactions have been described for atl; see below and in the gene report for atl.

[updated Sep. 2016 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 3A
OMIM report

[SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT; SPG3A](https://omim.org/entry/182600)

Human gene(s) implicated

[ATLASTIN GTPase 1; ATL1](https://omim.org/entry/606439)

Symptoms and phenotype

This subtype of hereditary spastic paraplegia is associated with lower limb weakness and spasticity that is generally slowly progressive. HSP3A usually develops in early childhood with more than 80% of affected individuals developing spastic gait before 10 years of age. Later-onset cases are associated with more slowly progressive disease. Some individuals may develop urinary bladder hyperactivity, axonal neuropathy and/or distal muscle wasting. [from NORD: Hereditary Spastic Paraplegia; 2016.09.02]

Genetics

Autosomal dominant spastic paraplegia 3A (SPG3A) is caused by heterozygous mutation in the ATL1 gene; incomplete penetrance is observed in some pedigrees. [from OMIM:182600; 2016.09.02]

Cellular phenotype and pathology
Molecular information

Atlastin-1 (ATL1) encodes a dynamin-related GTPase, which plays a role in formation of the tubular endoplasmic reticulum (ER) network and in axon elongation in neurons (Zhu et al., 2006, pubmed:16537571; Orso et al., 2009, pubmed:19633650). from OMIM:606439; 2016.09.02]

External links
Disease synonyms
SPG3A
spastic paraplegia 3, autosomal dominant
Strumpell disease
familial spastic paraplegia, autosomal dominant 1
FSP1
hereditary spastic paraplegia 3A
HSP3A
spastic paraplegia type 3A
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)

    Many to one: 4 human to 1 Drosophila. The additional human genes are ATL2, ATL3, and RNF112.

    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      Gene Snapshot
      atlastin (atl) encodes a dynamin-like membrane-bound GTPase that mediates endoplasmic reticulum membrane fusion in a GTP-dependent fashion. It is required for normal growth of muscles and synapses at the neuromuscular junction. [Date last reviewed: 2018-11-08]
      Gene Groups / Pathways
      Comments on ortholog(s)

      One to many: Dmel\atl is a high-scoring ortholog of human ATL1 and ATL2; it is a lower-scoring ortholog of ATL3 and a much low scoring ortholog of RNF112 (1 Drosophila to 4 human). Dmel\atl shares 52-57% identity and 71-77% similarity with ATL1, ATL2, and ATL3.

      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 (4 groups)
        protein-protein
        Interacting group
        Assay
        References
        cosedimentation, molecular weight estimation by staining, x-ray crystallography, cross-linking study, anti tag coimmunoprecipitation, anti tag western blot, fluorescent resonance energy transfer, enzymatic study
        experimental knowledge based
        pull down, anti tag western blot
        anti tag coimmunoprecipitation, peptide massfingerprinting, western blot
        Alleles Reported to Model Human Disease (Disease Ontology) (5 alleles)
        Models Based on Experimental Evidence ( 5 )
        Modifiers Based on Experimental Evidence ( 1 )
        Allele
        Disease
        Interaction
        References
        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
        amorphic allele - genetic evidence
        CRISPR/Cas9
        loss of function allele
        P-element activity
        References (15)