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General Information
Name
spastic paraplegia 76
FlyBase ID
FBhh0000510
Disease Ontology Term
Parent Disease
Overview

This report describes spastic paraplegia 76 (SPG76), which is a subtype of spastic paraplegia; SPG76 is inherited as an autosomal recessive. The human gene implicated in this disease is calpain 1 (CAPN1) which encodes one of many calpains (calcium-activated proteases) in humans. There are two Drosophila orthologs, CalpB and CalpA, for which classical amorphic alleles, RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated.

The human CAPN1 gene has not been introduced into flies.

Neither CalpB nor CalpA is an essential gene in flies: animals homozygous for amorphic mutations of either are viable and fertile. CalpB is implicated in normal cell migration. Neuronal knockdown of CalpB effected by RNAi results in progressive locomotor defects. CalpA appears to play a role in myoblast fusion. Overexpression of CalpA in muscle cell progenitors results in partial embryonic lethality; overexpression in transverse muscles allows survival to larval stages, but results in impaired locomotor behavior. Several physical and genetic interactions for both fly genes have been reported; see below and in the gene reports for CalpB and CalpA.

[updated Mar. 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 76
OMIM report

[SPASTIC PARAPLEGIA 76, AUTOSOMAL RECESSIVE; SPG76](https://omim.org/entry/616907)

Human gene(s) implicated

[CALPAIN 1; CAPN1](https://omim.org/entry/114220)

Symptoms and phenotype

See general description of spastic paraplegia above. SPG76 is characterized by young-adult onset of slowly progressive spasticity of the lower limbs resulting in gait difficulties. Most affected individuals have upper limb involvement and additional features such as foot deformities and dysarthria. [from OMIM:616907; 2017.03.03]

Genetics

Autosomal recessive hereditary spastic paraplegia-76 (SPG76) is caused by homozygous or compound heterozygous mutation in the CAPN1 gene (autosomal recessive). [from OMIM:616907; 2017.03.03]

Cellular phenotype and pathology
Molecular information

The calpains, calcium-activated neutral proteases, are non-lysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. CAPN1 encodes the large subunit of the ubiquitous enzyme, calpain 1. [Gene Cards; CAPN1; 2017.03.03]

Calpain (calcium-dependent protease) is an intracellular protease that requires calcium for its catalytic activity. [from OMIM:114220; 2017.03.03]

External links
Disease synonyms
SPG76
spastic paraplegia 76, autosomal recessive
autosomal recessive hereditary spastic paraplegia 76
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    Symbol / Name
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)

    Many to many (multiple human to 2 Drosophila).

    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (2)
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)

      High- to moderate-scoring ortholog of human CAPN9, CAPN2, CAPN1, CAPN3, CAPN8, and others (2 Drosophila to multiple human). CalpB shares 44-45% identity and 62-64% similarity with CAPN9, CAPN2, and CAPN1.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      Calpain-A (CalpA) encodes a calcium-dependent modulatory protease that cleaves its substrates in a limited fashion. During patterning and division in the blastoderm embryo, CalpA product cleaves the NF-κB inhibitor and the cell cycle regulator encoded by cact and CycB, respectively. CalpA product also regulates dendritic prunning of sensory neurons. [Date last reviewed: 2018-09-13]
      Gene Groups / Pathways
      Comments on ortholog(s)

      High- to moderate-scoring ortholog of human CAPN9, CAPN8, CAPN2, CAPN1, CAPN3, and others (2 Drosophila to multiple human). CalpA shares 41-44% identity and 57-60% similarity with CAPN9, CAPN8, CAPN2, and CAPN1.

      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 (10 groups)
        protein-protein
        Interacting group
        Assay
        References
        anti tag coimmunoprecipitation, anti tag western blot, western blot, anti bait coimmunoprecipitation
        anti tag coimmunoprecipitation, anti tag western blot
        anti tag coimmunoprecipitation, anti tag western blot
        enzymatic study, western blot, anti bait coimmunoprecipitation
        anti tag coimmunoprecipitation, anti tag western blot
        protein-protein
        Interacting group
        Assay
        References
        anti tag coimmunoprecipitation, anti tag western blot
        anti tag coimmunoprecipitation, anti tag western blot, western blot, anti bait coimmunoprecipitation
        anti bait coimmunoprecipitation, anti tag western blot
        anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation
        anti bait coimmunoprecipitation, anti tag western blot
        pull down, western blot, anti bait coimmunoprecipitation, bio-layer interferometry, predetermined participant, anti tag coimmunoprecipitation, anti tag western blot
        Alleles Reported to Model Human Disease (Disease Ontology) (12 alleles)
        Models Based on Experimental Evidence ( 1 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 5 )
        Models Based on Experimental Evidence ( 0 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 6 )
        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
        P-element activity
        piggyBac activity
        amorphic allele - genetic evidence
        P-element activity
        amorphic allele - molecular evidence
        P-element activity
        References (5)