Open Close
General Information
Name
spastic paraplegia 10
FlyBase ID
FBhh0000037
Disease Ontology Term
Parent Disease
Overview

This report describes spastic paraplegia 10 (SPG10), which is a subtype of spastic paraplegia; SPG10 exhibits autosomal dominant inheritance. The human gene implicated in this disease is KIF5A, a kinesin heavy chain gene. KIF5A is one of three human genes orthologous to the Drosophila gene Khc. Classical amorphic and loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis are available for Dmel\Khc.

The human KIF5A gene has not been introduced into flies.

Amorphic (null) mutations of Dmel\Khc are lethal when homozygous. SPG10 is modeled by an allele of Khc with a missense mutation that corresponds to a variant that is associated with spastic paraplegia in the human gene. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): N262S in the fly Khc gene (corresponds to N256S in the human KIF5A gene). Genetic and physical interaction(s) of the Dmel\Khc gene and protein product have been described; see below and in the gene report for Khc.

[updated Jan. 2017 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 10
OMIM report
[SPASTIC PARAPLEGIA 10, AUTOSOMAL DOMINANT; SPG10](http://omim.org/entry/604187)
Human gene(s) implicated
[KINESIN FAMILY MEMBER 5A; KIF5A](http://omim.org/entry/602821)
Symptoms and phenotype
Although 100% penetrant in the families studied, age of onset of SPG10 was variable, ranging from early childhood to 30 years old. It is slowly progressive and follows a rather benign course, with patients retaining the ability to walk (Schule, et al., 2008, pubmed:18245137).
See general description of spastic paraplegia above. Most cases of SPG10 meet the criteria of uncomplicated SPG, but some may involve additional neurological symptoms.
Most cases of SPG10 represent a pure form of HSP with late onset. Complex forms may occur with additional symptoms including upper limb amyotrophy, intellectual disability, hearing loss and retinitis pigmentosa. Parkinsonism, with symptoms such as tremor, abnormal slowness of movement and an inability to remain in a stable or balanced position, may also occur. Onset can range from infancy to mid-adulthood. [from NORD: Hereditary Spastic Paraplegia; 2016.09.02]
Genetics
SPG10 is a relatively rare form among SPG patients in Europe (Schule, et al., 2008, pubmed:18245137).
SPG10 is inherited as an autosomal dominant; it is caused by mutations in the KIF5A gene, a member of the kinesin-1 family. [from OMIM:604187; 15.06.30]
Cellular phenotype and pathology
KIF5A is expressed exclusively in neurons. [from OMIM:602821; 15.06.30]
Molecular information
KIF5A encodes a kinesin heavy chain; kinesins are microtubule-based motor proteins involved in the transport of organelles. In neurons, kinesins are essential for intracellular movement of membranous organelles and other macromolecular cargo from the neuronal cell body to the distal tip of the axon. All initially characterized SPG10 mutations were located in the motor domain of the KIF5A protein. [from OMIM:602821; 15.06.30]
External links
Disease synonyms
SPG10
spastic paraplegia
SPG
hereditary spastic paraplegia
HSP
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)
    Many to one: many human to 1 Drosophila; additional human orthologous genes are KIF5B and KIF5C.
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      Gene Snapshot
      Kinesin heavy chain (Khc) encodes the force generating subunit of kinesin-1, a microtubule motor protein. It functions in the long-distance transport of cytoplasmic "cargoes" such as mRNAs, protein complexes, and organelles. [Date last reviewed: 2019-03-14]
      Gene Groups / Pathways
      Comments on ortholog(s)
      Ortholog of human genes KIF5A, KIF5B and KIF5C (1 Drosophila to many human). Dmel\Khc shares 60% identity and 76% similarity with human KIF5A; 61% identity and 77% similarity with human KIF5B; and 61% identity and 77% similarity with human KIF5C.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Synthetic Gene(s) Used (0)
      Summary of Physical Interactions (21 groups)
      protein-protein
      Interacting group
      Assay
      References
      enzymatic study, fluorescence technology, inferred by author, x-ray crystallography, cross-linking study, molecular weight estimation by staining, cosedimentation, fluorescent resonance energy transfer
      anti tag coimmunoprecipitation, cross-linking study, Identification by mass spectrometry
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, western blot, two hybrid
      two hybrid, anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation
      anti tag coimmunoprecipitation, western blot, anti tag western blot, anti bait coimmunoprecipitation, experimental knowledge based, Identification by mass spectrometry
      pull down, western blot
      anti bait coimmunoprecipitation, western blot, pull down
      anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation
      pull down, western blot
      anti tag coimmunoprecipitation, anti tag western blot, western blot
      anti bait coimmunoprecipitation, western blot, enzymatic study, autoradiography
      anti tag coimmunoprecipitation, western blot
      anti bait coimmunoprecipitation, western blot, pull down
      experimental knowledge based
      anti tag coimmunoprecipitation, western blot, Identification by mass spectrometry, anti tag western blot, pull down
      anti tag coimmunoprecipitation, cross-linking study, Identification by mass spectrometry
      pull down, western blot, two hybrid, anti tag coimmunoprecipitation, anti tag western blot
      Alleles Reported to Model Human Disease (Disease Ontology) (8 alleles)
      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
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      ethyl methanesulfonate
      References (9)