This report describes spastic paraplegia 4 (SPG4), which is a subtype of spastic paraplegia; SPG4 exhibits autosomal dominant inheritance. The human gene implicated in this disease is SPAST (Spastin), which encodes an ATP-dependent microtubule severing protein and shares sequence similarity with the N-terminal MIT (microtubule interacting and trafficking) domain of the protein associated with SPG20. There is a single fly ortholog, spas, for which classical amorphic and loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple different UAS constructs of the human Hsap\SPAST gene have been introduced into flies, including wild-type and genes carrying mutational lesions implicated in SPG4. Heterologous rescue (functional complementation) of some aspects of the phenotype of a Dmel\spas null mutation has been demonstrated, including an increase in survival to adulthood. Variant(s) implicated in human disease tested (as transgenic human gene, SPAST): the K388R, C448Y, S44L, P45Q, and R431(term) variant forms of the human gene have been introduced into flies.
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): K467R (in isoform used) in the fly spas gene (corresponds to K388R in the human SPAST gene).
Variant(s) implicated in human disease tested (as analogous mutation in fly spas gene in Drosophila cell culture; FBrf0187332): designated D655N (corresponds to D555N in the human SPAST gene); designated K488R (corresponds to K388R in the human SPAST gene); designated E542A (corresponds to E442A in the human SPAST gene); designated S462C (corresponds to S362C in the human SPAST gene).
Amorphic (null) mutations of spas are semi-lethal; animals that survive to adulthood die within a week of eclosion and exhibit locomotor defects; larvae exhibit neural defects. Genetic interactions have been characterized, using the amorphic spas mutant phenotypes. Physical interaction(s) of the Dmel\spas protein product have been described; see below and in the gene report for spas.
[updated Aug. 2019 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 4, AUTOSOMAL DOMINANT; SPG4](https://omim.org/entry/182601)
See general description of spastic paraplegia above. The age of onset and the severity of symptoms both vary widely in cases of SPG4. [from OMIM:182601; 15.06.30]
SPG4 is the most common form of autosomal dominant HSP, accounting for approximately 45% of cases. Affected individuals have slowly progressive muscle weakness and spasticity. In rare cases, some individuals may have a complex form associated with seizures, ataxia, memory impairment, cognitive decline and dementia. Hand tremor and upper limb spasticity have also been reported. Onset can range from infancy to older adulthood. [from NORD: Hereditary Spastic Paraplegia; 2016.09.02]
SPG4 is inherited as an autosomal dominant; it is caused by mutations in the SPAST (spastin) gene. SPG4 is the most common form of autosomal dominant hereditary SPG, comprising up to 45% of cases (Svenson et al., 2001, pubmed:11309678; Crippa et al., 2006, pubmed:16682546). [from OMIM:182601; 15.06.30]
SPAST encodes an ATP-dependent microtubule severing protein and is a member of the AAA ATPase family. Microtubule severing may promote reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. SPAST is required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and for completion of the abscission stage of cytokinesis, and may also play a role in axon growth and the formation of axonal branches. [UniProtKB accession Q9UBP0; RefSeq accession NM_014946]