Alternative titles; symbols
HGNC Approved Gene Symbol: SPAST
Cytogenetic location: 2p22.3 Genomic coordinates (GRCh38) : 2:32,063,556-32,157,637 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p22.3 | Spastic paraplegia 4, autosomal dominant | 182601 | Autosomal dominant | 3 |
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), which they named 'spastin' (SPAST). The deduced spastin protein contains 616 amino acids and has a molecular mass 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. SPAST 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 SPAST, which has 96% sequence identity with human SPAST between amino acids 113 and 616. Spast transcripts are ubiquitously expressed in adult tissues and from embryonic day 7 to 17 in mouse.
Using a novel reporter system, Beetz et al. (2004) identified 2 independently functional nuclear localization sequences in human spastin.
Hazan et al. (1999) determined that the SPAST gene occupies approximately 90 kb of genomic DNA and contains 17 putative exons.
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 SPAST 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 (ATL1; 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.
Zhang et al. (2007) found that overexpression of katanin, spastin, or fidgetin eliminated MTs in interphase Drosophila S2 cells, suggesting that all 3 proteins function as MT-severing enzymes. Katanin, spastin, and fidgetin were targeted to both centrosomes and chromosomes in Drosophila spindles. Centrosomal localization of all 3 proteins was independent of MTs, but chromosomal targeting of the proteins was more complex, as each displayed distinct targeting within spindles. By targeting to spindles, spastin and fidgetin stimulated microtubule minus-end depolymerization by disassociating MTs from centrosomes, and they stimulated poleward flux in metaphase spindles. Furthermore, spastin and fidgetin stimulated turnover of alpha-tubulin (see 602529) at the ends of spindle MTs, catalyzed turnover of gamma-tubulin at centrosomes, and regulated the number of plus ends in preanaphase spindles. In contrast, katanin functioned primarily on anaphase A chromosomes, where it stimulated microtubule plus-end depolymerization and pacman-based chromatid motility. However, all 3 proteins were incorporated into the pacman-flux machinery and were required for chromosome segregation during anaphase A.
Using immunoprecipitation studies, Montenegro et al. (2012) showed that spastin interacted with RTN2B (603183). Cellular expression of ATPase-defective spastin redistributed the ER onto abnormally thickened and elongated microtubule bundles, and RTN2B was also redistributed onto these bundles. The findings indicated that RTN2 participates in the network of hairpin loop-containing ER morphogens, including REEP1 (609139), atlastin-1 (ATL1; 606439), and spastin.
Vietri et al. (2015) showed that the ESCRT-III complex, which promotes membrane constriction and sealing during receptor sorting, virus budding, cytokinesis, and plasma membrane repair, is transiently recruited to the reassembling nuclear envelope during late anaphase. ESCRT-III and its regulatory AAA (ATPase associated with diverse cellular activities) ATPase VPS4 (609982) are both specifically recruited by the ESCRT-III-like protein CHMP7 (611130) to sites where the reforming nuclear envelope engulfs spindle microtubules. Subsequent association of another ESCRT-III-like protein, IST1 (616434), directly recruits the AAA ATPase spastin (604277) to sever microtubules. Disrupting spastin function impairs spindle disassembly and results in extended localization of ESCRT-III at the nuclear envelope. Interference with ESCRT-III functions in anaphase is accompanied by delayed microtubule disassembly, compromised nuclear integrity, and the appearance of DNA damage foci in subsequent interphase. Vietri et al. (2015) proposed that ESCRT-III, VPS4, and spastin cooperate to coordinate nuclear envelope sealing and spindle disassembly at nuclear envelope-microtubule intersection sites during mitotic exit to ensure nuclear integrity and genome safeguarding, with a striking mechanistic parallel to cytokinetic abscission.
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.
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 spastic paraplegia and 6 control individuals. Using this technique, they identified heterozygous mutations in 5 families (see 604277.0001-604277.0005) with spastic paraplegia-4 (SPG4; 182601). Three unrelated affected individuals originating from the same area in Switzerland were heterozygous for a mutation in the acceptor splice site of SPAST 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.
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 (ATL1; 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 termination 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.
Using a combination of multiplex ligation-dependent probe amplification (MLPA) and array CGH, Boone et al. (2014) identified and mapped breakpoint junctions of 54 copy number variants (CNVs) in the SPAST gene that were found in patients with SPG. Most (70%) of the CNVs were mediated by an Alu-based mechanism. Twelve deletions (22%) overlapped part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects' genomes. Cell lines derived from 1 individual with a SPAST final exon deletion contained multiple SPAST:SLC30A6 (611148) fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. The findings provided evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional, and possibly phenotypic, consequences.
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.
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.
In a member of a family with spastic paraplegia-4 (SPG4; 182601), Hazan et al. (1999) identified a heterozygous 1210C-G transversion in exon 7 of the SPAST gene, resulting in a ser362-to-cys (S362C) substitution.
In a member of a family with spastic paraplegia-4 (SPG4; 182601), Hazan et al. (1999) identified a heterozygous 1468G-A transition in exon 11 of the SPAST gene, resulting in a cys448-to-tyr (C448Y) substitution.
Qiang et al. (2019) generated transgenic mice expressing 1 or 2 copies of human spastin bearing the pathogenic C448Y mutation. Transgenic mice showed no developmental defects or behavioral abnormalities until adulthood, when they showed gait impairment that was more severe in males than females. Immunofluorescence analysis revealed progressively abnormal axonal morphology in spinal cords of transgenic mice. The authors proposed that the phenotype was due to gain-of-function toxicity of the mutant spastin, as the phenotype was not seen in spastin-knockout mice; the M1 isoform of spastin accumulated in cerebral cortex and spinal cord of transgenic mice, but not wildtype mice; transgenic mice had significantly reduced microtubule stability in spinal cord, opposite to what would be expected with haploinsufficiency; the C448Y mutant spastin did not behave in a dominant-negative fashion; and the C448Y mutant spastin induced lysosomal transport deficits in cultured cortical neurons from transgenic mice that were exacerbated by knockdown of endogenous spastin and could be rescued by tetrabromocinnamic acid.
In a member of a family with spastic paraplegia-4 (SPG4; 182601), Hazan et al. (1999) identified a heterozygous 1-bp deletion (1520delT) in exon 11 of the SPAST gene, which would result in a premature termination codon at amino acid position 466. If stable, this protein would be truncated at 465 amino acids.
In a member of a family with spastic paraplegia-4 (SPG4; 182601), Hazan et al. (1999) identified a heterozygous 1620C-T transition in exon 13 of the SPAST gene, resulting in an arg499-to-cys(R499C) substitution. This mutation was identified in family 618.
Svenson et al. (2001) identified heterozygosity for the R499C mutation in another family segregating SPG4.
In 3 unrelated individuals from 3 kindreds with autosomal dominant spastic paraplegia-4 (SPG4; 182601), Hazan et al. (1999) identified a heterozygous A-to-G mutation in the acceptor splice site of intron 15 of the SPAST gene, resulting in the skipping of exon 16 followed by subsequent frameshift in the aberrant transcript. Each of the individuals originated from the same area of Switzerland, suggesting that these kindreds have a common ancestor.
In a member of a family with spastic paraplegia-4 (SPG4; 182601), Fonknechten et al. (2000) identified a heterozygous A-to-T transversion at nucleotide 873 in exon 5 of the SPAST gene, resulting in a premature termination codon at amino acid position 229 (lys229 to ter; K229X).
In a member of a family with spastic paraplegia-4 (SPG4; 182601), Fonknechten et al. (2000) identified a heterozygous single base insertion of A after nucleotide 578 in exon 2 of the SPAST gene, resulting in a premature termination codon 2 amino acids downstream from the insertion.
In a family with autosomal dominant spastic paraplegia (SPG4; 182601), Burger et al. (2000) used direct sequencing of the PCR product corresponding to exon 11 to demonstrate heterozygosity for an A-to-G substitution at the first nucleotide of the exon. This alteration caused an asp441-to-gly (D441G) substitution in the Walker B motif of the peptide. Within this motif of 6 amino acids (IIFIDE), the fifth position is D (aspartic acid) in 8 known proteins that exhibit high homology to spastin (Hazan et al., 1999). Aspartic acid is very polar and thus nearly always found on the outside of proteins, whereas glycine is nonpolar and tends to be on the inside.
In a 5-generation Italian family with pure autosomal dominant spastic paraplegia (SPG4; 182601) that showed marked intrafamilial variability in both age of onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55, Santorelli et al. (2000) identified a G-to-C substitution at nucleotide 1853+1 of the SPAST gene. This heterozygous mutation alters the consensus donor splice site of SPAST intron 16, resulting in an aberrant transcript with a longer exon 16 and a premature termination codon at amino acid 578. This produces a protein shortened by 38 amino acids in its conserved C terminus, removing part of the spastin AAA cassette (amino acids 577-599) and presumably causing loss of function.
Svenson et al. (2001) found a splice site mutation (ivs9+4A-G) in an affected member of a family with spastic paraplegia (SPG4; 182601). This 'leaky,' or partially penetrant, mutation was present in heterozygous state. A full-length, normally spliced transcript as well as an abnormally spliced transcript was produced from the mutant allele of the patient.
Svenson et al. (2001) described another 'leaky' mutation, an IVS11+2T insertion, in a patient with spastic paraplegia (SPG4; 182601), causing skipping of exon 11 in the SPAST gene. This insertion would shift the basepairing by 1 nucleotide, resulting in a net loss of 4 basepairs relative to the pairing with the wildtype sequence. Despite this drastic alteration in heterogeneous nuclear RNA pairing, this mutation, in its full genomic-sequence context, is only partially penetrant. Both normally and aberrantly spliced transcripts were produced from the mutant allele.
In a Korean family with typical clinical features of pure autosomal dominant hereditary spastic paraplegia-4 (SPG4; 182601), Ki et al. (2002) found a heterozygous T-to-A substitution at nucleotide 1031 in exon 7 of the spastin gene. The alteration caused an ile334-to-lys (I344K) substitution, which affected the third amino acid of the highly conserved AAA cassette domain.
In affected members of 9 families with spastic paraplegia (SPG4; 182601) originating from southern Scotland, Orlacchio et al. (2004) identified a heterozygous 1157A-G transition in exon 8 of the SPAST gene, resulting in an asn386-to-ser (N386S) substitution. Haplotype analysis suggested a founder effect. The N386S mutation is located within a conserved region in the spastin Walker motif A. In vitro functional expression studies showed that the mutant protein bound to a subset of microtubules which were reorganized in thick perinuclear bundles.
In a patient with a mild form of spastic paraplegia (SPG4; 182601), Lindsey et al. (2000) identified a homozygous 256C-T transition in exon 1 of the SPAST gene, resulting in a ser44-to-leu (S44L) substitution. The patient had never been able to run, but was otherwise asymptomatic until age 60 years, when he began to have gait abnormalities and lower limb spasticity. There was no family history of the disorder.
Svenson et al. (2004) found the L44 allele at a frequency of less than 0.6% (5 of 900 alleles) in a North American control population, indicating that it is a rare polymorphism.
In affected individuals from 3 unrelated SPG4 families, Svenson et al. (2004) identified compound heterozygosity for the S44L substitution and another disease-causing mutation in the SPAST gene (see, e.g., 604277.0016). Patients with both the disease-causing mutation and the S44L change had a significantly earlier age at disease onset than affected family members who carried only the disease-causing mutation. Two individuals who carried only a single S44L allele were asymptomatic. Using a bioinformatics approach, Svenson et al. (2004) found that the highly conserved S44 residue is likely a phosphorylation target site of cyclin-dependent kinases. The authors concluded that the S44L polymorphism acts as a phenotypic modifier of SPG4.
In a female child with severe infantile-onset SPG4, Chinnery et al. (2004) identified compound heterozygosity for 2 mutations in the SPAST gene: S44L and a missense mutation. The proband's father, who was mildly affected, had the S44L mutation; the mother, who was unaffected, and the maternal grandfather, who was severely affected, had the other mutation. Chinnery et al. (2004) concluded that the severe phenotype in the child resulted from 2 codominant mutations. The authors also noted that the mother remained unaffected despite having an SPAST mutation.
McDermott et al. (2006) identified a heterozygous S44L change in 2.8% of SPG individuals and in 3.1% of healthy controls, indicating that it is a polymorphism. Two of 3 individuals heterozygous for the S44L variant showed lower motor neuron dysfunction on EMG examination. The authors suggested that S44L may act as a weak mutation, causing a noncritical reduction in spastin activity that only becomes clinically significant when combined with another defect in motor neuron function.
In 6 affected members spanning 3 generations of a family with spastic paraplegia (SPG4; 182601), Svenson et al. (2004) identified a heterozygous 1534A-T transversion in the SPAST gene, resulting in an asp470-to-val (D470V) substitution. The 3 patients with only the heterozygous D470V mutation had adult onset at ages 55, 40, and 18 years, respectively, whereas 3 patients who were compound heterozygous for the D470V mutation and the S44L (604277.0015) polymorphism had disease onset in infancy, were wheelchair-bound by age 40 years, had a stutter, and had mild to moderate cognitive deficits. Svenson et al. (2004) concluded that presence of the S44L polymorphism, in addition to the D470V mutation, modified the SPG4 phenotype in this family.
Svenson et al. (2004) identified a 259C-A transversion in the SPAST gene, resulting in a pro45-to-gln (P45Q) substitution, at a frequency of less than 0.2% (1 of 900 alleles) in a North American control population, indicating that it is a rare polymorphism.
In 2 affected members of a family with spastic paraplegia (SPG4; 182601), Svenson et al. (2004) identified compound heterozygosity for the P45Q polymorphism and a disease-causing arg562-to-gly mutation in the SPAST gene (R562G; 604277.0018). These 2 patients had disease onset in infancy, whereas affected members with only the disease-causing R562G mutation had significantly later onset. Two family members who carried only the P45Q polymorphism were unaffected. Svenson et al. (2004) concluded that the P45Q polymorphism was a modifier of the SPG4 phenotype.
In 11 affected members spanning 3 generations of a family with spastic paraplegia (SPG4; 182601), Svenson et al. (2004) identified a heterozygous arg562-to-gly (R562G) substitution in the SPAST gene. Two of the 11 patients, who were compound heterozygous for the R562G mutation and the pro45-to-gln polymorphism (P45Q; 604277.0017), had disease onset in infancy, whereas 7 of 9 patients who had only the D470V mutation had later onset at ages ranging from 17 to 58 years. Two family members who carried only the P45Q polymorphism were asymptomatic. The authors concluded that inheritance of the P45Q polymorphism, when present with the disease-causing R562G mutation, modified the SPG4 phenotype in this family.
In 6 affected members of a Japanese family with a relatively mild form of spastic paraplegia (SPG4; 182601), Iwanaga et al. (2005) identified a heterozygous 2,307-bp deletion in the SPAST gene. The deletion spanned from the 5-prime UTR, 114-bp upstream of the translation initiation site, to 1.8-kb downstream of the exon 1 splice donor site. The results suggested that the primary SPAST mRNA transcript lacked the entire coding region of exon 1, including the translation initiation site and the donor site of exon 1, leading to defective splicing and subsequent rapid mRNA degradation. The structural abnormality was detected by Southern blot analysis followed by deletion-specific PCR amplification.
In a woman with spastic paraplegia (SPG4; 182601), Schickel et al. (2006) identified a heterozygous 1216A-G transition in exon 9 of the SPAST gene. Although the mutation was predicted to result in an ile406-to-val (I406V) substitution, RT-PCR and direct sequencing of lymphocyte-derived cDNA revealed a 30-bp in-frame deletion of nucleotides 1216 to 1245 in exon 9, corresponding to deletion of codons 406 to 415. Thus, the 1216A-G transition created a fully dominant ectopic splice donor site. Transfection experiments in human cells showed that the mutant spastin protein with the deletion showed normal subcellular localization but lacked microtubule-severing activity, consistent with haploinsufficiency. A mutant construct containing the I406V substitution showed subcellular localization and microtubule-severing activity that was similar to wildtype spastin protein, suggesting that the predicted amino acid substitution was not pathogenic.
In a patient with a severe form of spastic paraplegia-4 (SPG4; 182601), McDermott et al. (2006) identified a 1335C-A transversion in exon 11 of the SPAST gene, resulting in a ser445-to-arg (S445R) substitution. He 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. The findings of bulbar and respiratory involvement, as well as lower motor neuron degeneration, broadened the phenotype associated with mutations in the SPAST gene.
In affected individuals of a large Brazilian kindred with spastic paraplegia-4 (SPG4; 182601), originally reported by Starling et al. (2002), Mitne-Neto et al. (2007) identified a heterozygous tandem duplication of exons 10 through 12 of the SPAST gene. Long-range PCR and sequencing showed nonhomology of the sequences contributing to the novel fusion. The duplication was predicted to result in premature termination and disruption of enzymatic activity. Twelve 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.
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