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]
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]
[SPASTIC PARAPLEGIA 12, AUTOSOMAL DOMINANT; SPG12](https://omim.org/entry/604805)
[RETICULON 2; RTN2](https://omim.org/entry/603183)
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]
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]
Many to many: 4 human to 2 Drosophila; additional human orthologous genes are RTN1, RTN3, RTN4.
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.