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General Information
Name
spastic paraplegia 12
FlyBase ID
FBhh0000038
Disease Ontology Term
Parent Disease
Overview

This report describes spastic paraplegia 12 (SPG12), which is a subtype of spastic paraplegia; SPG12 exhibits autosomal dominant inheritance. The human gene implicated in this disease is RTN2 (Reticulon 2), which produces both short and long protein isoforms. Reticulons are required for proper generation of tubular endoplasmic reticulum and appear to play a role in intracellular vesicular transport. There are four related reticulons in humans (RTN1, RTN2, RTN3, RTN4) and three similar reticulons in flies (Rtnl1, Rtnl2, CG42853). In flies, only Rtnl1 produces the long protein isoform(s) and is widely expressed. Dmel\Rtnl2 and the lower-scoring ortholog, CG42853, encode only short isoforms and exhibit restricted patterns of expression, confined primarily to the developing testis and adult testis. For Dmel\Rtnl1, classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

The human RTN2 gene has not been introduced into flies.

Loss-of-function mutations in the Dmel\Rtnl1 gene are viable and fertile, but display progressive locomotor defects and abnormal odor response. Physical interaction(s) of the Dmel\Rtnl1 protein product have been described; see below and in the gene report for Rtnl1.

[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 12
OMIM report

[SPASTIC PARAPLEGIA 12, AUTOSOMAL DOMINANT; SPG12](https://omim.org/entry/604805)

Human gene(s) implicated

[RETICULON 2; RTN2](https://omim.org/entry/603183)

Symptoms and phenotype

Spastic paraplegia 12 is characterized by lower limb spasticity and hyperreflexia, resulting in walking difficulties. Some patients may have urinary symptoms and distal sensory impairment. The age at onset is variable and can range from childhood to adulthood (summary by Montenegro et al., 2012, pubmed:22232211). [from OMIM:604805; 15.06.30]

Onset of SPG12 is usually between 7-14 years of age, but can occur earlier and has been report to occur well into adulthood. This form of spastic paraplegia is rapidly progressive and affected individuals often ultimately require a wheelchair. [from NORD: Hereditary Spastic Paraplegia; 2016.09.02]

Genetics

SPG12 is inherited as an autosomal dominant; it is caused by mutations in the RTN2 (Reticulon 2) gene. [from OMIM:604805; 15.06.30]

Cellular phenotype and pathology
Molecular information

Reticulons are necessary for proper generation of tubular endoplasmic reticulum and likely play a role in intracellular vesicular transport. [RefSeq accession NM_005619]

The RTN2 gene produces both short and long protein isoforms (Roebroek et al., 1998, pubmed:9693037); one of the long forms has been found to be localized to the endoplasmic reticulum and interacts with SPAST (causative gene of SPG4) (Montenegro et al., 2012, pubmed:22232211). [from OMIM:603183; 15.06.30]

External links
Disease synonyms
SPG12
spastic paraplegia
SPG
hereditary spastic paraplegia
HSP
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: 4 human to 2 Drosophila; additional human orthologous genes are RTN1, RTN3, RTN4.

    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      Gene Snapshot
      Reticulon-like1 (Rtnl1) encodes a reticulon family member, with predicted intramembrane hairpin domains that can insert into the cytosolic face of the endoplasmic reticulum (ER), thereby curving it and promoting ER tubule formation. It is enriched on tubular ER, including axons and egg chamber fusomes. [Date last reviewed: 2018-11-15]
      Molecular function (GO)
        Gene Groups / Pathways
          Comments on ortholog(s)

          Higher-scoring Drosophila ortholog of human genes RTN1, RTN2, RTN3, RTN4 (many Drosophila to many human). Dmel\Rtnl1 encodes both long and short isoforms; this is true of the four human reticulon genes, also. Dmel\Rtnl1 is broadly expressed; the long isoform Rtnl1-PH shares 25-30% identity and 41-46% similarity with the long isoforms of the human genes.

          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 (23 groups)
            Alleles Reported to Model Human Disease (Disease Ontology) (2 alleles)
            Models Based on Experimental Evidence ( 2 )
            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
            References (10)