| refine your query |
| genesymbol | type | description | chr. | startpos | endpos | synonyms | |
| SPAST | protein-coding | spastin | 2 | 32288680 | 32382706 | FSP2, ADPSP, KIAA1083, SPG4 | |
| links | NCBI ENSEMBL SwissProt GeneCards STRING PubMed create primers for all transcripts | ||||||
| Reactome pathways | VPS4 binds ESCRT-III assemblies at nuclear envelope (NE) fenestrations, SPAST (spastin) binds the IST1 subunit of ESCRT-III at the sites of microtubule attachment to chromatin, VPS4 mediates disassembly of ESCRTIII subunits to promote sealing of holes in the nuclear envelope, SPAST (spastin) mediates the severing of microtubules at chromosome attachment sites | ||||||
| PFAM | ATPase family associated with various cellular activities (AAA), MIT (microtubule interacting and transport) domain, Holliday junction DNA helicase ruvB N-terminus | ||||||
| InterPro domains | AAA+ ATPase domain, ATPase, AAA-type, core, ATPase, AAA-type, conserved site, MIT, Spastin, P-loop containing nucleoside triphosphate hydrolase | ||||||
| paralogs | FIGN (19%), FIGNL1 (28%), IQCA1 (12%) | ||||||
| HPO | |||||||
| OMIM | SPASTIC PARAPLEGIA 4, AUTOSOMAL DOMINANT; SPG4 synopsis: INHERITANCE: Autosomal dominant HEAD AND NECK: [Eyes]; Nystagmus (rare) GENITOURINARY: [Bladder]; Urinary urgency; Urinary incontinence; Sphincter disturbances SKELETAL: [Spine]; Lower back pain NEUROLOGIC: [Central nervous system]; Lower limb spasticity; Lower limb weakness; Spastic gait; Hyperreflexia; Extensor plantar responses; Pyramidal signs; Degeneration of the lateral corticospinal tracts; Cognitive decline; Memory impairment; Deficits in language expression; Deficits in abstraction; Mental retardation (rare); Dementia (rare); Arachnoid cysts of the cerebellopontine angle (reported in 1 family); [Peripheral nervous system]; Decreased vibratory sense in the lower limbs; [Behavioral/psychiatric manifestations]; Agitation; Aggression; Apathy; Depression; Disinhibition MISCELLANEOUS: Variable age of onset (infancy to 63 years); Insidious onset; Progressive disorder; Highly variable severity; Genetic anticipation; Most common form of autosomal dominant hereditary spastic paraplegia (accounts for 40% of SPG cases); Genetic heterogeneity, see SPG3A (182600) MOLECULAR BASIS: Caused by mutation in the spastin gene (SPG4, 604277.0001). text: A number sign (#) is used with this entry because autosomal dominant spastic paraplegia-4 results from mutation in the SPG4 gene (604277). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600). DESCRIPTION The hereditary spastic paraplegias (SPG, HSP) are a group of clinically and genetically diverse inherited disorders characterized predominantly by progressive 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') or with other neurologic abnormalities ('complicated'). Pure SPG4 is the most common form of autosomal dominant hereditary SPG, comprising up to 45% of cases (Svenson et al., 2001; Crippa et al., 2006). CLINICAL FEATURES In 5 of 7 French families and in 1 large Dutch pedigree with a form of autosomal dominant familial spastic paraplegia, Hazan et al. (1994) found linkage to a locus, which they termed FSP2 (also known as SPG4), on chromosome 2p. This finding distinguished the disease from autosomal dominant spastic paraplegia-3 (182600), which had been mapped to chromosome 14. Age of onset in the 6 families showing linkage to 2p varied widely within families and the mean age at onset ranged from 20 to 39 years. Thus, age of onset may be a poor criterion for classifying autosomal dominant spastic paraplegia. Anticipation in the age of onset was observed in 2 of the kindreds. Durr et al. (1996) reported 12 families with autosomal dominant spastic paraplegia linked to the SPG4 locus on chromosome 2. Age of onset ranged from infancy to 63 years. The clinical expression of the disorder within a family included asymptomatic patients who were unaware of their condition, mildly affected individuals who had spastic gait but were able to walk independently, and severely affected patients who were wheelchair bound. Durr et al. (1996) commented on the extensive intra- and interfamilial clinical variation. Nielsen et al. (1998) evaluated 5 families with 2p-linked pure spastic paraplegia. In 2 families, nonprogressive 'congenital' spastic paraplegia was seen in some affected members, whereas adult-onset progressive spastic paraplegia was present in others. Low backache was reported as a late symptom by 47% of the 63 at-risk members in the 5 families. Brain and total spinal cord MRI disclosed no significant abnormalities. Nielsen et al. (1998) concluded that SPG4 is a phenotypically heterogeneous disorder, characterized by both interfamilial and intrafamilial variation. Nance et al. (1998) found striking variation in clinical features in 4 families with spastic paraplegia with linkage to chromosome 2 markers. Only mild neurologic signs were observed in some subjects. The clinical features of 1 family had previously been described by Boustany et al. (1987). Onset was generally in the third to fifth decades with an average onset age of 35 years (range, 5 to 61 years). All clearly affected patients had scissoring gait, and in all who were examined at least 2 of the following were found: extensor plantar responses, increased knee and ankle reflexes, increased tone, muscle spasms, or leg cramps. Urinary urgency or other symptoms compatible with a neurogenic bladder, leg weakness, and decreased vibration sense were present in some but not all patients. Byrne et al. (1997, 1998) presented a family with autosomal dominant hereditary spastic paraplegia and a specific form of cognitive impairment who showed linkage to the SPG4 locus on chromosome 2. The pattern of cognitive impairment in this family was characterized primarily by deficits in visual-spatial functions. Dysfunction manifested itself by difficulty in carrying out new tasks, forgetfulness, poor spatial perception, and impaired visual-motor coordination. By haplotype analysis the presence of the mutant gene was identified in an individual who, at the age of 57, had the same pattern of cognitive impairment but no spastic paraplegia. Furthermore, 6 individuals who presented with the disease haplotype had normal neurologic and neuropsychologic examinations. All 6 were below the maximal age of onset in the family, namely, 60 years. In this Irish family the cognitive impairment was considered to be a manifestation of the SPG4 gene mutation. Reid et al. (1999) investigated 35 individuals from 4 families of Welsh origin, 22 of whom had 'pure' hereditary spastic paraplegia, for the presence of subclinical cognitive impairment. They found significant reductions in scores on the Mini-Mental State Examination (MMSE) among affected individuals compared to controls. To assess whether the lower MMSE scores were restricted to subjects older than 50 years, scores for affected subjects 50 years of age or younger were compared to those of controls. A significant difference in score remained. One of the families was linked to the chromosome 2 locus, while 2 others showed linkage to none of the loci known at that time. There was no significant difference between the results of these 2 groups. McMonagle et al. (2000) compared the phenotypic expressions of autosomal dominant hereditary spastic paresis in several families with a mutation in the SPG4 gene and several families without a mutation in SPG4. In the mutation-positive group, age of onset was later, disability score was greater, progression of disease was faster, wheelchair use was greater (40.9% vs 4.8% in the mutation-excluded group), there was greater abnormal vibration sensation in the lower limbs (68.2% vs 19%), and fewer individuals were asymptomatic (18.2% vs 42.9%). Dementia was more prevalent in the mutation-positive group. McMonagle et al. (2000) emphasized the finding of cognitive impairment as a feature of SPG4 mutations. White et al. (2000) reported a patient with familial SPG4 who had clinical dementia. Postmortem neuropathologic examination showed neuronal loss and tau- (MAPT; 157140) immunoreactive neurofibrillary tangles in the hippocampus and tau-immunoreactive balloon cells in the limbic area and neocortex. Lewy bodies were present in the substantia nigra. White et al. (2000) suggested that these findings confirmed an association of dementia with SPG4. McMonagle et al. (2004) used several measures of cognitive function to assess 11 patients from 3 families in whom SPG4 was confirmed by genetic analysis or linkage. SPG4 patients scored significantly lower on the Cambridge cognitive examination (CAMCOG) (mean score of 73.5 compared to 91.7 in controls). After approximately 3 years, the patients' mean score fell to 64.4, whereas the mean control score declined slightly to 90.8. Deficits in the SPG4 patients were noted in attention, language expression, memory, and abstraction. Behavior assessment found that SPG4 patients exhibited agitation, aggression, apathy, irritability, depression, and disinhibition. Accounting for age, McMonagle et al. (2004) concluded that subtle changes in cognitive function in patients with SPG4 may begin after age 40 years, with more severe decline after age 60. Orlacchio et al. (2004) reported 32 patients from 9 families from southern Scotland with SPG4. Age at onset varied from 11 to 53 years. In addition to classic features of hereditary spastic paraplegia, 2 of the 32 patients had mental retardation and 2 other patients had a thin corpus callosum and cerebellar atrophy. All affected members had the same mutation in the SPG4 gene (604277.0014), and haplotype analysis suggested a founder effect. Orlacchio et al. (2004) reported a large Italian family in which all 16 members who had SPG4 also had congenital arachnoid cysts at the cerebellopontine angle ranging in size from 21 to 31 mm. Six patients also had mental retardation. Genetic analysis confirmed a mutation in the SPG4 gene. McDermott et al. (2006) reported a patient with SPG4 who developed walking difficulties in his late teens with deteriorating gait in his 20s; he was wheelchair-dependent at age 35. He later developed stiffness in the upper limbs, bladder dysfunction, dysarthria, and swallowing difficulties. In his 40s, he developed respiratory insufficiency and distal muscle wasting in the lower limbs. Molecular analysis identified a mutation in the SPG4 gene (S445R; 604277.0021). The findings of bulbar and respiratory involvement, as well as lower motor neuron degeneration, broadened the phenotype associated with mutations in the SPG4 gene. Orlacchio et al. (2008) reported a large 4-generation Italian family with SPG4 confirmed by genetic analysis. The mean ages at onset were 17.5 and 18.8 years for symptoms of the lower and upper limbs, respectively. There was a general impression of genetic anticipation spanning the 4 generations. All affected individuals had spasticity of the lower limbs and pyramidal tract signs such as hyperreflexia, extensor plantar responses, or both, and pes cavus. All patients also had weak intrinsic hand muscles, with severe amyotrophy most relevant in the thenar eminence. Peroneal muscle wasting was reported in five patients, and many used a cane. Other associated features included impaired vibration sensation and cognitive dysfunctions. All patients except 1 had temporal lobe epilepsy with partial complex seizures associated with hippocampal sclerosis. Murphy et al. (2009) reported a family in which 12 members had SPG4 due to a deletion of exon 17 in the SPG4 gene (Beetz et al., 2007). Cognitive assessment performed over a 7-year period found that all 4 patients who were older than 60 years developed mild to moderate cognitive decline. Two younger patients aged 48 and 40, respectively, had mild cognitive impairment. Genetic analysis of this family was unusual because 4 patients with the SPG4 deletion also carried a microdeletion in the NIPA1 gene (608145), which causes SPG6 (600363); only 2 of these 4 had cognitive impairment. Five patients with only the SPG4 deletion had cognitive impairment, including 2 who did not have clinical signs of SPG. Another family member with only the NIPA1 microdeletion lacked clinical signs of SPG or cognitive impairment at age 57. Murphy et al. (2009) concluded that SPG4 is associated with cognitive decline, and that the SPG6 microdeletion does not have a clinical phenotype in this family. Postmortem examination of the proband, who had both deletions as well as SPG and cognitive impairment, showed a markedly atrophic spinal cord with degeneration of the corticospinal tracts, and superficial spongiosis and widespread ubiquitin-positive inclusions in the neocortex and white matter. MAPPING In 5 French families and 1 large Dutch pedigree with autosomal dominant spastic paraplegia, Hazan et al. (1994) found linkage markers in the 2p24-p21 region. An analysis of recombination events and multipoint linkage placed this form of the disease within a 4-cM interval flanked by loci D2S400 and D2S367. In 4 Caucasian North American families and in 1 family from Tunisia, Hentati et al. (1994) found linkage of late-onset SPG to DNA markers on chromosome 2p in 4 of the families. Pathologic findings in a member of one of the chromosome 2-linked families had previously been reported by Sack et al. (1978). Scott et al. (1997) examined 11 Caucasian pedigrees with autosomal dominant 'uncomplicated' familial spastic paraplegia for linkage to the previously identified loci on 2p, 14q (SPG3A), and 15q (SPG6; 600363). Chromosome 15q was excluded for all families. Five families showed evidence for linkage to 2p, 1 family to 14q, and 5 families remained indeterminate. Recombination events reduced the 2p minimum candidate region to a 3-cM interval between D2S352 and D2S367, and supported the previously reported 7-cM minimum candidate region for 14q. Age of onset was highly variable, indicating that subtypes of SPG are more appropriately defined on a genetic basis than by age of onset. Comparison of age of onset in parent-child pairs was suggestive of anticipation, with a median difference of 9.0 years (p less than 0.0001). MOLECULAR GENETICS Using the repeat expansion detection (RED) method, Nielsen et al. (1997) analyzed 21 affected individuals from 6 SPG4 Danish families linked to 2p24-p21. They found that 20 of 21 affected individuals showed CAG repeat expansions of the SPG4 gene (604277.0006) versus 2 of 21 healthy spouses, demonstrating a strongly statistically significant association between the occurrence of the repeat expansion and the disease. Presumably, CAG repeat expansion is involved as a dynamic mutation in SPG4. They estimated the expansion to be equal to or greater than 60 CAG repeat copies in the affected individuals. Benson et al. (1998) analyzed 20 familial spastic paraplegia families, including 4 for which there was evidence for linkage to the SPG4 region on 2p24-p21, and found that in most cases the repeat expansion detected by the RED method was due to nonpathogenic expansions of the chromosome 18q21.1 SEF2-1 locus (TCF4; 602272) or the 17q21.3 ERDA1 locus (603279). Polymorphic expansions at SEF2-1 and ERDA1 appeared frequent and can confound RED studies in the search for genes causing disorders demonstrating anticipation. In 6 SPG families, however, the CAG repeat expansion was detected in a subset of affected and at-risk individuals that did not result from expansion of either of these loci. Overall, 11 of 37 (30%) of the SPG patients with a CAG/CTG repeat expansion were unaccounted for by the SEF2-1 and ERDA1 loci, compared with 2 of 23 (9%) of the unaffected at-risk individuals and none of 19 controls. In the majority of cases the novel expansions were shorter than those previously reported. Fonknechten et al. (2000) analyzed DNA from 87 unrelated patients with autosomal dominant hereditary spastic paraplegia and detected 34 novel mutations scattered along the coding region of the SPG4 gene. They found missense (28%), nonsense (15%), and splice site point (26.5%) mutations as well as deletions (23%) and insertions (7.5%). Mean age at onset was 29 +/- 17 years, with a range of 0 to 74 years. Disease severity was highly variable among patients, and disease progression was actually faster in the late-onset group. Penetrance was age-dependent and incomplete even in older mutation carriers (85% after 40 years). Six percent of 238 mutation carriers were asymptomatic, while 20% of carriers were unaware of their symptoms. There was no difference in either age of onset or clinical severity among groups of patients with missense mutations versus truncation mutations. Svenson et al. (2001) stated that pure hereditary spastic paraplegia type 4 is the most common form of autosomal dominant hereditary SPG. They screened the spastin gene (604277) for mutations in 15 families showing linkage to the SPG4 locus and identified 11 mutations, 10 of which were novel. In 15 of 76 unrelated individuals with hereditary spastic paraplegia, Meijer et al. (2002) identified 5 previously reported mutations and 8 novel mutations in the SPG4 gene. Svenson et al. (2004) identified 2 rare polymorphisms in the SPG4 gene: ser44 to leu (S44L; 604277.0015) and pro45 to gln (P45Q; 604277.0017). In affected members of 4 SPG4 families, the presence of either the S44L or P45Q polymorphism in addition to a disease-causing SPG4 mutation (see, e.g., 604277.0016; 604277.0018) resulted in an earlier age at disease onset. Svenson et al. (2004) concluded that the S44L and P45Q polymorphisms, though benign alone, modified the SPG4 phenotype when present with another SPG4 mutation. Depienne et al. (2006) identified 19 different mutations in the SPG4 gene in 18 (12%) of 146 unrelated mostly European patients with progressive spastic paraplegia. Most of the patients had no family history of the disorder. In 13 (26%) of 50 unrelated Italian patients with pure hereditary spastic paraplegia (HSP), Crippa et al. (2006) identified 12 different mutations in the SPG4 gene, including 8 novel mutations. All 5 of the familial cases analyzed carried an SPG4 mutation, confirming that the most common form of autosomal dominant HSP is caused by mutations in this gene. Eight (18%) of 45 sporadic patients had a SPG4 mutation. No mutations were identified in 10 additional patients with complicated HSP. Genotype-phenotype correlations were not observed. In 24 (20%) of 121 probands with autosomal dominant SPG in whom mutations in the SPG4 gene were not detected by DHPLC, Depienne et al. (2007) identified 16 different heterozygous exonic deletions in the SPG4 gene using multiplex ligation-dependent probe amplification (MLPA). The deletions ranged in size from 1 exon to the whole coding sequence. The patients with deletions showed a similar clinical phenotype as those with point mutations but an earlier age at onset. The findings confirmed that haploinsufficiency of SPG4 is a major cause of autosomal dominant SPG and that exonic deletions account for a large proportion of mutation-negative SPG4 patients, justifying the inclusion of gene dosage studies in appropriate clinical scenarios. Depienne et al. (2007) stated that over 150 different pathogenic mutations in the SPG4 gene had been identified to date. Using MLPA analysis, Beetz et al. (2007) identified partial deletions of the SPG4 gene in 7 of 8 families who had been linked to the region, but in whom mutation screening had not identified mutations. The families had been previously reported by Lindsey et al. (2000), McMonagle et al. (2000), Meijer et al. (2002), and Svenson et al. (2001). The findings indicated that large genomic deletions in SPG4 are not uncommon and should be part of a workup for autosomal dominant SPG. Mitne-Neto et al. (2007) identified a heterozygous tandem duplication of exons 10 through 12 of the SPG4 gene (604277.0022) in affected individuals of a large Brazilian kindred with spastic paraplegia, originally reported by Starling et al. (2002). In this family, Starling et al. (2002) noted that there were 24 affected men and only 1 affected woman, but X-linked inheritance was ruled out. The authors found strong linkage to the SPG4 locus, but no mutations were identified in the coding region of the SPG4 gene. The results of Mitne-Neto et al. (2007) thus confirmed the diagnosis of SPG4. At the time of the latter report, 12 of 30 mutation carriers had no clinical complaints. Among these patients, 9 of 14 female carriers had no complaints, indicating sex-dependent penetrance in this family, with women being partially protected. Shoukier et al. (2009) identified SPG4 mutations in 57 (28.5%) of 200 unrelated, mostly German patients with SPG. There were 47 distinct mutations identified, including 29 novel mutations. In a review of other reported mutations, the authors found that most (72.7%) of the mutations were clustered in the C-terminal AAA domain of the SPG4 gene. However, clustering was also observed in the MIT (microtubule interacting and trafficking), MTBD (microtubule-binding domain), and an N-terminal region (residues 228 to 269). In the original cohort of 57 patients, there was a tentative genotype-phenotype correlation indicating that missense mutations were associated with an earlier onset of the disease. NOMENCLATURE Hazan et al. (1993) referred to the form of autosomal dominant spastic paraplegia encoded by a gene on chromosome 14q as FSP1, and Hazan et al. (1994) referred to the form encoded by a gene on chromosome 2p as FSP2. The genes for these 2 disorders are also symbolized SPG3 and SPG4, respectively. See report at OMIM's website. SPASTIN; SPAST text: CLONING Using a positional cloning strategy based on the spastic paraplegia-4 (SPG4; 182601) candidate region on chromosome 2p22-p21, Hazan et al. (1999) identified a gene encoding a member of the AAA protein family (see 601681) that they named 'spastin' (SPAST). The spastin open reading frame encodes a 616-amino acid protein of approximately 67.2 kD. The AAA cassette is located between amino acids 342 and 599. The 3 conserved ATPase domains include Walker motifs A and B. Spastin and related members of its AAA subgroup contain leucine zipper motifs, which in spastin occur at amino acid positions 50-78 and 508-529. The spastin C terminus has strong homology to several members of the AAA family. Comparison of amino acid sequences of spastin and mitochondrial metalloproteinases showed that homology is restricted to the AAA cassette. Spastin shows only 29% identity between amino acid positions 342 and 599 with paraplegin (602783); paraplegin shows 57% identity with yeast Afg3p over the same region, suggesting that spastin does not belong to the same AAA subfamily as do paraplegin and other metalloproteinases. SPG4 is ubiquitously expressed in human adult and fetal tissue, showing slightly higher expression in fetal brain. Hazan et al. (1999) cloned the mouse ortholog of SPG4, which between amino acids 113 and 616 has 96% identity with human SPG4. Spg4 transcripts are ubiquitously expressed in adult tissues and from embryonic day 7 to 17 in mouse. GENE STRUCTURE Hazan et al. (1999) determined that SPG4 gene occupies approximately 90 kb of genomic DNA and contains 17 putative exons. GENE FUNCTION By expressing wildtype or ATPase-defective spastin in several cell types, Errico et al. (2002) showed that spastin interacts with microtubules. Interaction with the cytoskeleton was mediated by the N-terminal region of spastin and was regulated through the ATPase activity of the AAA domain. Expression of missense mutations (including 604277.0001, 604277.0002, and 604277.0004) into the AAA domain led to constitutive binding to microtubules in transfected cells and induced the disappearance of the aster and the formation of thick perinuclear bundles, suggesting a role of spastin in microtubule dynamics. Consistently, wildtype spastin promoted microtubule disassembly in transfected cells. The authors suggested that spastin may be involved in microtubule dynamics similarly to the highly homologous microtubule-severing protein katanin (606696). The authors hypothesized that impairment of fine regulation of the microtubule cytoskeleton in long axons, due to spastin mutations, may underlie the pathogenesis of hereditary spastic paraplegia. By multiple sequence alignment, Ciccarelli et al. (2003) identified a domain of approximately 80 amino acids shared by spastin and spartin (607111), the molecule that is mutated in the Amish type of hereditary spastic paraplegia (SPG20; 275900). The domain is a slightly expanded version of a domain that is a well established and consistent feature of molecules with a role in endosomal trafficking. Both spastin and spartin are likely to be involved in microtubule interaction. Ciccarelli et al. (2003) proposed a new descriptive name MIT (contained within microtubule-interacting and trafficking molecules) for the domain and predicted endosomal trafficking as the principal functionality of all molecules in which it is present. In neuronal and nonneuronal cells expressing spastin, McDermott et al. (2003) found that the wildtype protein was localized to the perinuclear area within the cell soma, whereas mutant spastin was found throughout the cytoplasm consistent with cytoskeletal staining, as well as extending into the axons, but not the dendrites. Transfection of proteins into the cells suggested that normal spastin acts as a microtubule-severing protein and that mutant spastin colocalizes with, but does not sever, microtubules. The abnormal interaction of mutant spastin with microtubules was associated with abnormal cellular distribution of mitochondria and peroxisomes. McDermott et al. (2003) suggested that the disruption of organelle transport on the microtubule cytoskeleton, including transport to distal axons, may be the primary disease mechanism in SPG4. Errico et al. (2004) demonstrated that spastin was enriched in cell regions containing dynamic microtubules. During cell division spastin was found in the spindle pole, the central spindle, and the midbody, whereas in immortalized motoneurons it was enriched in the distal axon and the branching points. Spastin interacted with the centrosomal protein NA14 (SSNA1; 610882), and cofractionated with gamma-tubulin (TUBG1; 191135). Deletion of the region required for binding to NA14 disrupted spastin interaction with microtubules, suggesting that NA14 may be an important adaptor to target spastin activity at the centrosome. Errico et al. (2004) hypothesized that spastin may play a role in cytoskeletal rearrangements and dynamics. Using a yeast 2-hybrid approach, Reid et al. (2005) identified CHMP1B (606486), a protein associated with the ESCRT (endosomal sorting complex required for transport)-III complex, as a binding partner of spastin. CHMP1B and spastin proteins showed clear cytoplasmic colocalization in transfected cells; CHMP1B and spastin proteins interacted specifically in vitro and in vivo in complementation assays, and spastin coimmunoprecipitated with CHMP1B. The interaction was mediated by a region of spastin lying between residues 80 and 196 and containing an MIT domain. Expression of epitope-tagged CHMP1B in mammalian cells prevented the development of the abnormal microtubule phenotype associated with expression of ATPase-defective spastin. The authors suggested a role for spastin in intracellular membrane traffic events, and proposed that defects in intracellular membrane traffic may be a significant cause of motor neuron pathology. Svenson et al. (2005) developed a novel antiserum corresponding to a portion of exon 6 of the SPG4 gene that was specific for all spastin isoforms. Using this reagent, the authors found that endogenous spastin was located at the centrosome in a variety of cell types at all points in the cell cycle. Spastin remained localized at the centrosome even after microtubule depolymerization, suggesting that spastin is an integral centrosomal protein. Spastin was also enriched at discrete clusters in dendrites, axons, and glial projections of rat hippocampal neurons. Svenson et al. (2005) concluded that spastin plays a role in microtubule dynamics and organization. Independently, Evans et al. (2006) and Sanderson et al. (2006) demonstrated that the N-terminal domain of spastin bound directly to the C-terminal cytoplasmic domain of atlastin (SPG3A; 606439), suggesting that the 2 gene products interact in a common biologic pathway. Evans et al. (2006) used yeast 2-hybrid analysis and coimmunoprecipitation studies in HeLa cells, and Sanderson et al. (2006) used yeast 2-hybrid analysis of a human fetal brain cDNA library and protein pull-down, coimmunoprecipitation, and colocalization studies in HeLa cells, HEK293T cells, and mouse NSC34 neuronal cells. By yeast 2-hybrid analysis and coimmunoprecipitation studies in mouse fibroblast cells (NIH3T3) and HeLa cells, Mannan et al. (2006) demonstrated that spastin interacts with reticulon-1 (RTN1; 600865), which is primarily expressed in the endoplasmic reticulum. The interaction is mediated through the spastin N-terminal region, which contains a microtubule-interacting and trafficking domain. Intracellular distribution studies showed colocalization of the 2 proteins in discrete cytoplasmic vesicles. The findings strengthened the hypothesis that disruption of intracellular vesicular transport processes may underlie spastic paraplegia. BIOCHEMICAL FEATURES - Crystal Structure Roll-Mecak and Vale (2008) reported the x-ray crystal structure of the Drosophila spastin AAA domain and provided a model for the active spastin hexamer generated using small-angle x-ray scattering combined with atomic docking. The spastin hexamer forms a ring with a prominent central pore and 6 radiating arms that may dock onto the microtubule. Helices unique to the microtubule-severing AAA ATPases surround the entrances to the pore on either side of the ring, and 3 highly conserved loops line the pore lumen. Mutagenesis revealed essential roles for these structural elements in the severing reaction. Peptide and antibody inhibition experiments further showed that spastin may dismantle microtubules by recognizing specific features in the carboxy-terminal tail of tubulin. Roll-Mecak and Vale (2008) concluded that their data supported a model in which spastin pulls the C terminus of tubulin through its central pore, generating a mechanical force that destabilizes tubulin-tubulin interactions within the microtubule lattice. MOLECULAR GENETICS Hazan et al. (1999) amplified and sequenced overlapping cDNA fragments spanning the entire spastin open reading frame from 1 individual of each of 14 families affected with SPG4 and 6 control individuals. Using this technique, they identified heterozygous mutations in 5 families (see 604277.0001-604277.0005). Three unrelated affected individuals originating from the same area in Switzerland were heterozygous for a mutation in the acceptor splice site of SPG4 intron 15 (604277.0005). Fonknechten et al. (2000) analyzed DNA from 87 unrelated autosomal dominant hereditary spastic paraplegia patients and detected 34 novel mutations scattered along the coding region of the SPG4 gene (see, e.g., 604277.0007 and 604277.0008). They found missense (28%), nonsense (15%), and splice site point (26.5%) mutations as well as deletions (23%) and insertions (7.5%). Six percent of 238 mutation carriers were asymptomatic, while 20% of carriers were unaware of their symptoms, indicating reduced penetrance. There was no difference in either age of onset or clinical severity among groups of patients with missense mutations versus truncation mutations. Using the repeat expansion detection (RED) method, Nielsen et al. (1997) analyzed 21 affected individuals from 6 SPG4 Danish families linked to 2p24-p21. They found that 20 of 21 affected individuals showed CAG repeat expansions of the SPG4 gene versus 2 of 21 healthy spouses, suggesting a strongly statistically significant association between the occurrence of the repeat expansion and the disease. Hazan et al. (1999), however, constructed a detailed high-resolution integrated map of the SPG4 locus that excluded the involvement of a CAG repeat expansion in SPG4-linked autosomal dominant spastic paraplegia. They noted that an analysis of 20 autosomal dominant hereditary spastic paraplegia families, including 4 linked to the SPG4 locus, by Benson et al. (1998) had demonstrated that most repeat expansions detected by the RED method were caused by nonpathogenic expansions at the 18q21.1 SEF2 (602272) and 17q21.3 ERDA1 (603279) loci. Burger et al. (2000) identified 4 novel SPG4 mutations in German families with autosomal dominant hereditary spastic paraplegia, including 1 large family for which anticipation had been proposed (Burger et al., 1996). Since no trinucleotide repeat expansion was found in this family but instead a D441G missense mutation (604277.0009), the authors presumed that the clinically observed anticipation was due to ascertainment bias. Svenson et al. (2001) screened the spastin gene for mutations in 15 families consistent with linkage to the SPG4 locus and identified 11 mutations, 10 of which were novel (see, e.g., 604277.0011-604277.0012). Five of the mutations were in noninvariant splice junction sequences. RT-PCR analysis of mRNA from patients showed that each of these 5 mutations resulted in aberrant splicing. One mutation was found to be 'leaky,' or partially penetrant; the mutant allele produced both mutant (skipped exon) and wildtype (full-length) transcripts. The existence of at least one leaky mutation suggested that relatively small differences in the level of wildtype spastin expression can have significant functional consequences. This may account, at least in part, for the wide ranges in age at onset, symptom severity, and rate of symptom progression that occurs both among and within families with SPG linked to SPG4. Sauter et al. (2002) analyzed the spastin gene in SPG patients from 161 apparently unrelated families in Germany and identified mutations in 27 of the families. Only 3 of the mutations had previously been described and only 1 of the mutations was found in 2 families. Among the detected mutations were 14 frameshift, 4 nonsense, and 4 missense mutations, 1 large deletion spanning several exons, and 4 splice mutations. Most of the novel mutations were located in the conserved AAA cassette-encoding region of the spastin gene. The relative frequency of spastin gene mutations in an unselected group of German hereditary spastic paraplegia patients was approximately 17%; frameshift mutations accounted for most SPG4 mutations in the population. The proportion of splice mutations was considerably lower than that reported elsewhere (Lindsey et al., 2000; Svenson et al., 2001). In 15 of 76 unrelated individuals from North America with hereditary spastic paraplegia (HSP), Meijer et al. (2002) identified 5 previously reported mutations and 8 novel mutations in the SPG4 gene: 4 missense, 1 nonsense, 1 frameshift, and 2 splice site mutations. Charvin et al. (2003) used anti-spastin polyclonal antibodies to identify 2 isoforms of 75 and 80 kD in both human and mouse tissues, with a tissue-specific variability of the isoform ratio. Spastin is an abundant protein in neural tissues and immunofluorescence microscopy analysis revealed expression in neurons but not in glial cells. These data suggested that axonal degeneration linked to SPG4 mutations may be caused by a primary defect of neurons. Protein and transcript analyses of patients carrying either nonsense or frameshift SPG4 mutations revealed neither truncated protein nor mutated transcripts, providing further evidence that these mutations are responsible for a loss of spastin function. Svenson et al. (2004) identified 2 rare polymorphisms in the SPG4 gene: ser44 to leu (S44L; 604277.0015) and pro45 to gln (P45Q; 604277.0017). In affected members of 4 SPG4 families, the presence of either the S44L or P45Q polymorphism in addition to a disease-causing SPG4 mutation (see, e.g., 604277.0016; 604277.0018) resulted in an earlier age at disease onset. Svenson et al. (2004) concluded that the S44L and P45Q polymorphisms, though benign alone, modified the SPG4 phenotype when present with another SPG4 mutation. In 8 of 18 Korean patients with spastic paraplegia, Park et al. (2005) identified 8 different mutations in the SPG4 gene. Seven of the 8 patients had a family history of the disorder. No mutations were identified in the SPG3A gene (606439). Brugman et al. (2005) identified 6 mutations in the SPG4 gene in 6 (13%) of 47 unrelated patients with adult-onset upper motor neuron symptoms restricted to the legs. A seventh SPG4 mutation was identified in a 34-year-old woman with rapidly progressive spastic tetraparesis and pseudobulbar dysarthria consistent with a diagnosis of amyotrophic lateral sclerosis (ALS; see 105400). However, no spastin mutations were identified in 51 additional patients with upper motor neuron involvement of the arms or bulbar regions, suggesting that spastin mutations are not a common cause of ALS. In 13 (26%) of 50 unrelated Italian patients with pure hereditary spastic paraplegia (HSP), Crippa et al. (2006) identified 12 different mutations in the SPG4 gene, including 8 novel mutations. All 5 of the familial cases analyzed carried an SPG4 mutation, confirming that the most common form of autosomal dominant HSP is caused by mutations in this gene. Eight (18%) of 45 sporadic patients had an SPG4 mutation. No mutations were identified in 10 additional patients with complicated HSP. Genotype-phenotype correlations were not observed. In 24 (20%) of 121 probands with autosomal dominant SPG in whom mutations in the SPG4 gene were not detected by DHPLC, Depienne et al. (2007) identified 16 different heterozygous exonic deletions in the SPG4 gene using multiplex ligation-dependent probe amplification (MLPA). The deletions ranged in size from 1 exon to the whole coding sequence. The patients with deletions showed a similar clinical phenotype as those with point mutations but an earlier age at onset. The findings confirmed that haploinsufficiency of SPG4 is a major cause of autosomal dominant SPG and that exonic deletions account for a large proportion of mutation-negative SPG4 patients, justifying the inclusion of gene dosage studies in appropriate clinical scenarios. Depienne et al. (2007) stated that over 150 different pathogenic mutations in the SPG4 gene had been identified to date. McDermott et al. (2006) identified 44 different mutations in the SPG4 gene, including 27 novel mutations, in 53 (19%) of 285 individuals with spastic paraplegia. The majority of mutations occurred within the conserved AAA cassette or were predicted to cause premature truncation or missplicing within the AAA cassette. The heterozygous S44L change was identified in 8 (2.8%) of 285 SPG individuals and in 3.1% of healthy controls, indicating that it is a polymorphism. Beetz et al. (2006) identified partial deletions in the SPG4 gene in 12 (18%) of 65 patients with spastic paraplegia who had previously been regarded as spastin mutation-negative based on direct sequencing. The authors suggested that partial spastin deletions act via haploinsufficiency. Using MLPA analysis, Beetz et al. (2007) identified partial deletions of the SPG4 gene in 7 of 8 families who had been linked to the region, but in whom mutation screening had not identified mutations. The families had been previously reported by Lindsey et al. (2000), McMonagle et al. (2000), Meijer et al. (2002), and Svenson et al. (2001). The findings indicated that large genomic deletions in SPG4 are not uncommon and should be part of a workup for autosomal dominant SPG. Beetz et al. (2007) reported a family in which spastic paraplegia segregated with a deletion of exon 1 of the SPG4 gene in the proband, her brother, and her 2 sons. Although the proband and her brother also had a deletion of the SPG3A gene, the SPG3A deletion did not segregate with the disorder in her sons and had no apparent effect on the severity of the disorder. The findings suggested that haploinsufficiency is the pathogenic mechanism for SPG4, whereas a dominant-negative effect is the pathogenic mechanism for SPG3A. Shoukier et al. (2009) identified SPG4 mutations in 57 (28.5%) of 200 unrelated, mostly German patients with SPG. There were 47 distinct mutations identified, including 29 novel mutations. In a review of other reported mutations, the authors found that most (72.7%) of the mutations were clustered in the C-terminal AAA domain. However, clustering was also observed in the MIT domain, MTBD, and an N-terminal region (residues 228 to 269). In the original cohort of 57 patients, there was a tentative genotype-phenotype correlation indicating that missense mutations were associated with an earlier onset of the disease. GENOTYPE/PHENOTYPE CORRELATIONS Ivanova et al. (2006) identified 5 different heterozygous mutations in the SPG4 gene in 6 of 36 unrelated Bulgarian patients with hereditary spastic paraplegia. All 6 probands with SPG4 mutations had affected family members. There were 2 missense mutations, 1 premature termination, and 2 splice site mutations. Affected individuals with the missense mutations had a significantly earlier mean age at onset (4.5 to 8 years) compared to the other patients (17.5 to 42.5 years). In addition, 3 affected members of 1 of the families with a missense mutation also had scoliosis. Ivanova et al. (2006) predicted that the splice site and truncation mutations decreased overall spastin function, implying haploinsufficiency as a pathogenic mechanism, whereas the missense mutations likely resulted in a dominant-negative pathogenic mechanism and a more severe phenotype. See report at OMIM's website. |
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| transcripts | ENST00000315285: 5117 bases (protein_coding) ENST00000345662: 5116 bases (protein_coding) |
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| If you feel that GeneDistiller has helped you in your research, please cite the following publication: Seelow D, Schwarz JM, Schuelke M. GeneDistiller--distilling candidate genes from linkage intervals. PLoS ONE. 2008;3(12):e3874. Epub 2008 Dec 5. |
| entity | last update (YYYY-MM-DD) |
| Disease Ontology | 2020-06-29 |
| Ensembl 84 (GRCh73) | 2016-06-14 |
| Ensembl:Entrez | 2021-10-28 |
| Entrez gene history | 2021-10-28 |
| Entrez gene positions | 2021-10-28 |
| Entrez gene RIFS | 2021-10-28 |
| Entrez genes | 2021-10-28 |
| Entrez gene synonyms | 2021-10-28 |
| HPO:Genes | 2015-12-22 |
| HPO:OMIM | 2015-12-22 |
| HPO:OrphaNet | 2015-12-22 |
| Human Phenotype Ontology | 2015-12-22 |
| OMIM | 2015-08-25 |